RARE DISEASE
Mucolipidosis
Mucolipidosis
Mucolipidosis
Drug discovery
1
drug
With orphan designation
Overview
Mucolipidosis (ML) encompasses rare autosomal recessive lysosomal storage disorders caused by defective trafficking of lysosomal enzymes due to GNPTAB, GNPTG, or MCOLN1 mutations [1][3][7]. ML types II/III (I-cell disease) involve skeletal dysplasia, developmental delay, cardiorespiratory complications, and progressive neurodegeneration, while ML IV features severe psychomotor impairment and retinal degeneration [1][7][15]. Diagnosis relies on elevated plasma lysosomal enzymes, genetic testing, and imaging showing dysostosis multiplex [1][6][12].
Therapies
Supportive care dominates: physical/occupational therapy, respiratory support, and corrective surgeries [1][9]. Bisphosphonates (e.g., alendronate) show efficacy in reducing pathologic bone resorption in ML II/III [3]. Experimental gene therapy for ML IV demonstrates improved CNS outcomes in preclinical models [13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism
Research Papers
232 drug discovery papers about Mucolipidosis, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
232 drug discovery papers about Mucolipidosis, with 2 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-08-05 | Clinical phenotype and GNPTAB gene mutation spectrum analysis of Chinese patients with mucolipidosis type II α/β.
Mucolipidosis type II α/β (ML II α/β) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the GNPTAB gene, leading to GlcNAc-1-phosphotransferase deficiency and subsequent accumulation of intracellular toxic substances. This study aimed to systematically describe the clinical spectrum and mutational characteristics of Chinese patients with ML II α/β to facilitate early diagnosis and provide ethnicity-specific data. Whole-exome sequencing (WES) was performed on a new proband, and a comprehensive literature review was conducted, summarizing a total of 56 Chinese cases (including 1 new case). All patients presented with skeletal deformities (100%), 96.4% had coarse facial features, 94.6% had developmental delay, and the median age at diagnosis was 17.5 months. The new proband carried compound heterozygous non-sense mutations NM_024312.4:c.2455G>T (p.Glu819*) and NM_024312.4:c.1123C>T (p.Arg375*) and died of respiratory failure at 27 months of age. Notably, NM_024312.4:c.1090C>T (p.Arg364*) was the most common mutation (found in 39.3% of patients), associated with typical skeletal abnormalities and early death. Cardiac abnormalities (16.1%) and pulmonary complications (12.5%) were common comorbidities. This study identified a unique mutational hotspot in Chinese patients with ML II α/β and revealed a severe phenotype with poor prognosis, primarily resulting in death from respiratory failure. These findings are beneficial for clinical diagnosis, genetic counseling, and targeted molecular screening of this disease.
2026-03-17 | Isolated cardiac mucolipidosis type III α/β mimicking Fabry’s disease: a case report highlighting the role of pathology and genetics in diagnosis
A 39-year-old female presented with left precordial pain and chest tightness following emotional stress approximately 10 years ago. Initial coronary angiography was unremarkable, though electrocardiogram revealed mild ST-T changes (Panel A). Over the past year, the symptoms became more frequent with reduced tolerance of physical activity, accompanied by mild elevation in cardiac troponin I (0.217–0.227 ng/mL, normal < 0.04) and T-wave inversion (Panel B). Cardiac magnetic resonance imaging revealed normal structure on cine four-chamber images (Panel C) and no late gadolinium enhancement (Panel D). Endomyocardial biopsy revealed extensive vacuolar degeneration under light microscopy (Panel E), loss of galactosidase expression on immunohistochemistry (Panel F), and myelin-like bodies accumulation under electron microscopy (Panel G). Fabry’s disease was suspected, but GLA gene sequencing and lyso-globotriaosylsphingosine came back negative. Whole-exome sequencing identified a pathogenic mutation (c.2715+1G>A) and a variant of uncertain significance (c.1702T>G) in GNPTAB gene. Elevated plasma lysosomal enzyme levels confirmed mucolipidosis (ML) type III α/β. Physical examination showed no skeletal abnormalities or characteristic facial features. The patient was diagnosed with MLIII α/β with early cardiomyopathy and managed supportively, with close cardiac monitoring for early signs of heart failure.
2025-11-20 | Differential ion selectivity and disease-associated dysfunction of TRPML channels revealed by patient and engineered mutants.
The endolysosomal transient receptor potential mucolipin (TRPML) channels play key roles in regulating lysosomal trafficking, signaling, and function. While mutations in TRPML1 cause mucolipidosis type IV (MLIV), the functional consequences of many disease-associated mutations remain unclear. In this study, we used live-cell confocal imaging in HeLa cells to comprehensively characterize the subcellular localization and cation (Ca2+ and Zn2+) permeability of TRPML1-3, 10 TRPML1 MLIV patient-derived mutants, and engineered pore mutants. We showed that TRPML1 and TRPML3 permeate both Ca2+ and Zn2+, whereas TRPML2 conducts only Ca2+. Subcellular localization analyses revealed that TRPML1 and TRPML2 localize predominantly to lysosomes, whereas TRPML3 is preferentially localized to the endoplasmic reticulum. Among the 10 patient-derived TRPML1 mutants, nine exhibited severely impaired agonist-mediated Ca2+ and Zn2+ permeability, indicating severe functional loss. In contrast, the F408Δ mutant, associated with a milder phenotype, retained partial ion permeability and was the only mutant capable of constitutive Ca2+ permeation without agonist stimulation. Interestingly, we found that nonfunctional, lysosome-localized TRPML1 mutants are associated with more severe disease phenotypes than those retained in the endoplasmic reticulum, suggesting that lysosomal localization of nonfunctional TRPML1 may have dominant-negative or toxic effects. Finally, through structure-guided mutagenesis, we generated a metal-selective TRPML1 mutant, I468V, that is permeable to Ca2+ but not to Zn2+, providing a new tool for dissecting the distinct physiological roles of Zn2+ and Ca2+ in TRPML1-mediated processes. Together, these findings provide new insights into how TRPML1 mutations disrupt subcellular localization, ion permeability, and selectivity, which contribute to the variable clinical spectrum of MLIV.
2025-06-09 | Exploring human plasma proteomic variations in mucolipidosis type IV.
Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.
2024-11-18 | Physiological and Pathological Functions of TRPML1
The lysosome is a nutrient recycling center and a sophisticated cellular signaling hub in the cell. It governs various cellular processes, including endocytosis, phagocytosis, and autophagy. Lysosomal dysfunction has been linked to a variety of human pathological conditions. The functions of lysosomes are controlled by not only digestive enzymes but also ion channels and ion transporters, a group of transmembrane proteins residing in the membrane of lysosomes. Among these ion channels and ion transporters, the transient receptor potential mucolipin 1 (TRPML1) channel is the major Ca2+-permeable channel that plays an important role in lysosome physiology. Mutations in TRPML1 have been associated with mucolipidosis type IV (ML-IV) disease. TRPML1 dysfunction has also been implicated in multiple pathological conditions. In this chapter, we will summarize and discuss the diverse functions of TRPML1 in lysosomes and other cellular processes under both physiological and pathological conditions.
small molecules
2026-06-20 | Zoledronic acid ameliorates multiple organ pathologies in a murine model of mucolipidosis II by partially restoring mannose-6-phosphate-mediated lysosomal hydrolase activities.
Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal hydrolases, and progressive multi-organ pathology. We generated a Gnptab p.R364X knock-in mouse model of MLII, which recapitulated the biochemical, skeletal, visceral, and neurological features of human MLII. Proteomic analysis of lysosomes isolated from MLII fibroblasts by LysoIP showed depletion or decrease of M6P-dependent hydrolases, upregulation of M6P-independent enzymes, and increased abundance of lysosomal membrane proteins. Zoledronic acid treatment increased both M6P-dependent and M6P-independent luminal hydrolases, and reduced glycosaminoglycan storage in MLII skin fibroblasts. Besides skeletal density improvement, Zoledronic acid, administered from 4 to 24 weeks to MLII mice, ameliorated multiple system manifestations, including articular cartilage degeneration, motor impairment, hepatomegaly, along with decreased urinary heparan sulfate and brain neuroinflammation. Our findings demonstrate that zoledronic acid ameliorates multiple system pathologies in MLII mice, which may be mediated, at least in part, through partial restoration of M6P-dependent proteins within lysosomes.
2026-05-03 | Peroxisome-derived ether lipids regulate lysosomal exocytosis.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
2026-01-01 | TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition
In pulmonary fibrosis lung tissue is thickened and scarred, and the lungs become progressively stiffer and smaller, leading to low levels of blood oxygen and shortness of breath. Lung fibrosis is not curable and life expectancy is reduced. Fibrosis is characterized by an increased accumulation of extracellular matrix (ECM) proteins such as collagen and elastin. ECM proteins are degraded predominantly by matrix metalloproteinases (MMPs). Here, we show that the lysosomal cation channel TRPML1, which causes the lysosomal storage disorder mucolipidosis type IV (MLIV) when mutated or lost, regulates the levels of MMPs in the ECM of mouse airways, modulating exocytosis of MMP2, 8, 9, 12, and 19, which mediate collagen/elastin degradation. While TRPML1 loss reduces MMP levels in lung macrophage and fibroblast supernatants, small molecule activation of TRPML1 results in increased levels. MLIV mice display a fibrosis-like lung phenotype similar to the phenotype evoked by bleomycin. We thus identify TRPML1 as a regulator of MMP release in the lung with loss of TRPML1 resulting in lung fibrosis due to excessive extracellular collagen and elastin accumulation.
2025-05-07 | Disruption of Man-6-P-Dependent Sorting to Lysosomes Confers IGF1R-Mediated Apoptosis Resistance.
Mutations in GNPTAB underlie mucolipidosis II and mucolipidosis III α/β, which are inherited lysosomal storage disorders caused by a defective UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine phosphotransferase. As a result, newly synthesized acid hydrolases fail to acquire Mannose-6-Phosphate (Man-6-P) sorting signals, or do so to a lesser extent, and exhibit an impaired trafficking to lysosomes. Interestingly, we found that GNPTAB knockout HeLa cells are resistant to several cytotoxic agents: doxorubicin, chloroquine, staurosporine and paclitaxel. While we detected an increased trapping of weak bases in the expanded lysosomal population of these cells, which could reduce the effect of doxorubicin and chloroquine; the decreased cell response to staurosporine and paclitaxel suggested the involvement of alternative resistance mechanisms. Indeed, further investigation revealed that the hyperactivation of the Insulin-like Growth Factor 1 Receptor (IGF1R) pathway is a central player in the apoptosis resistance exhibited by Man-6-P sorting deficient cells.
2025-02-19 | TPC2 in drug development: Emerging target for cancer, viral infections, cardiovascular diseases, and neurological disorders
The lysosomal two-pore channel 2 (TPC2) modulates intracellular calcium (Ca 2 + ) signaling and has been implicated in inflammatory, cardiovascular, and neurodegenerative conditions, as well as cancer and viral infections. Despite its potential as a drug target, TPC2 is still in the early stages of therapeutic development. The major challenges include achieving high target specificity without inducing unintended effects on other endolysosomal channels and on the crosstalk between TPC2 and other intracellular and extracellular Ca 2+ channels. Recent advancements in the structural analysis of TPC2, along with the development of TPC2 agonists and inhibitors, have significantly expanded our understanding of its mechanistic contributions to disease. This review highlights potential TPC2-based therapies for cancer, inflammation, and neurological disorders, emphasizing the need for further research to develop targeted TPC2 modulators and fully elucidate the molecular mechanisms of TPC2. • TPC2 modulates angiogenesis, proliferation, and metastasis, positioning it as a potential therapeutic target in oncology. • Dysregulated TPC2 signaling is implicated in lysosomal storage disorders, including Type IV mucolipidosis, underscoring its therapeutic relevance. • Future research aims to enhance TPC2 modulator specificity, elucidate its role in Ca²⁺ signaling crosstalk, and address context-dependent effects for translational applications.
cell therapies
2026-01-06 | Failure of Allogeneic Transplant to Correct Sialidosis Despite Early Diagnosis and Full Donor Engraftment of Non-Carrier Leucocytes.
Sialidosis, also known as Mucolipidosis Type I, is a rare condition caused by defects in the NEU1 gene which causes the accumulation of sialylated peptides, oligosaccharides, and glycoproteins leading to neurological decline. Haematopoetic stem cell transplantation has been performed in the symptomatic phase twice in the literature but has failed to prevent deterioration. We report on a case where a 4-year-old child was diagnosed with pre-symptomatic sialidosis due to investigation following the incidental detection of a cherry-red spot prior to the onset of neurological symptoms. We performed haematopoetic stem cell transplantation with a matched unrelated cord blood unit with optimal timing prior to clinical decline, achieving full donor engraftment with a largely uneventful post-transplant recovery followed by a period of relative clinical stability. However, subsequent neurological decline detailed by clinical history and radiological findings has occurred suggesting a lack of disease responsiveness to transplantation despite optimal timing. We go on to provide supporting laboratory investigations detailing sialidosis fibroblast culture as part of a novel cross-correction assay and compare results to other transplant responsive lysosomal storage disorders such as mucopolysaccharidosis type 1-H and detail a lack of cross-correction in concordance with our clinical findings. We conclude that conventional allogeneic haematopoetic stem cell transplantation is not a viable disease-modifying treatment option in sialidosis, even when performed optimally in the pre-symptomatic phase, and suggest that alternative treatment options must be explored to improve outcomes in this condition.
2025-09-26 | A Rare Case Report OF A Newborn That May Be Confused With Rickets Aad Other Metabolic Bone Dısorders: I-Cell Disease
I cell disease (Mucolipidosis II) is a rare autosomal recessive lysosomal storage disease characterised by severe skeletal abnormalities, intrauterine growth retardation, coarse facial appearance, progressive psychomotor retardation, thickening of the skin, gingival hyperplasia, hernias and early death. It is caused by a deficiency of N-acetylglucosamine 1-phosphotransferase which is normally found in the endoplasmic reticulum or Golgi apparatus. Since the clinical, biochemical and laboratory findings of the disease mimic rickets, the diagnosis may be difficult at the beginning
2024-12-23 | Clinical and molecular characteristics of 20 Chinese probands with Mucolipidosis type II and III alpha/beta.
Mucolipidosis (ML) II and III alpha/beta are lysosomal disorders caused by mutations in the GNPTAB gene which encodes the alpha and beta subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. To explore the clinical and molecular characteristics of the 20 ML II and III alpha/beta patients, clinical data was collected and GNPTAB gene was analyzed by nest PCR and direct Sanger-sequencing. The activity of several lysosomal enzymes was measured in the plasma. Among the 20 ML II and III alpha/beta patients, 6 patients were classified as ML II and 14 as ML III alpha/beta. The main clinical manifestations were joint stiffness, skeletal deformity, mental retardation and short stature. Bone X-ray examination showed radiological changes. The plasma arylsulfatase A and hexosaminidase A enzyme activities increased significantly. Urinary glycosaminoglycan values were normal. We detected mutations in GNPTAB in 35 of 40 alleles (87.5%). Mutation c.2715 + 1G > A and c.2404 C > T (p.Gln802Ter) were the most prevalent variants, accounting for 14.3% and 11.4%, respectively. Five novel mutations c.3335 + 5G > A, c.1284 + 1G > A, c.571 + 4 A > G, c.1634_1635delAA (p.Lys545Serfs*16) and c.1582T > C(p.Cys528Arg) were identified. Our study expands the spectrum of GNPTAB gene in China. Mutation c.2715 + 1G > A was the most prevalent mutation in our study. The novel mutation c.1284 + 1G > A might be a severe mutation associated with ML II.
2023-07-06 | Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations
Mucolipidosis type II (MLII), or I-cell disease, is a rare lysosomal storage disease (LSD) caused by variants in the GNPTAB gene. MLII patients exhibit clinical phenotypes in the prenatal or neonatal stage, such as marked dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, and mental and motor developmental abnormalities. The median age at diagnosis for MLII is 0.7 years, the median survival is 5.0 years, and the median age at death is 1.8 years. No cure for MLII exists.Sanger sequencing of the GNPTAB gene identified the compound heterozygous mutations c.673C > T in exon 7 and c.1090C > T in exon 9, which were novel double heterozygous mutations first reported in China. For the first time, we describe our experience in the use of HSCT for MLII. Our patient underwent HSCT with cells from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor at 12 months of age. Myeloid neutrophil and platelet engraftment occurred on Days 10 and 11, respectively.The patient's limb muscle tension was significantly reduced, and his gross and fine motor skills were improved four months after transplantation. DST(Developmental Screen Test) results showed that the patient's fine motor skills and mental development were improved compared with before HSCT.MLII is a very severe lysosomal storage disease, to date, only 3 cases have been reported on the use of HSCT to treat MLII. Our data show that HSCT is a potential way to prolong the life of patients and improve their quality of life. Due to the lack of comparable data and time, the exact benefit remains unclear in MLII patients. Longer-term follow-up and in-depth prospective studies are indispensable.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
gene therapies
2026-01-22 | Pneumothorax as a life‐threatening long‐term complication with mucolipidosis type II
The authors declare no conflicts of interest. The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2025-06-20 | Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain protein hypersialylation.
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III, and VII, which are associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of patients with neurological MPS and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A, β-galactosidase (GLB1), and glucosamine-6-sulfate sulfatase (GALNS), leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and induced pluripotent stem cell-derived (iPSC-derived) cortical neurons of patients with neurological MPS. Increased sialylation of N-linked glycans in brains of patients with MPS and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral (LV) gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioral traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe is a novel pathological pathway in the neurological MPS spectrum crucially contributing to CNS pathology.
2025-04-26 | Age-sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis II.
Mucolipidosis II (MLII) is a lysosomal storage disorder (LSD) caused by mutations in GNPTAB and loss of mannose 6-phosphate-dependent targeting of lysosomal enzymes. Affected children exhibit cognitive deficits, skeletal dysplasia, and cardiopulmonary disease, with death typically occurring before age 10. A naturally occurring feline model of MLII results from a nonsense mutation in GNPTAB; cats develop elevated lysosomal enzyme activities, growth retardation, skeletal deformities, blindness, cardiomegaly, and die prematurely. Most LSDs exhibit central nervous system disease, which is a primary contributor to morbidity and mortality. Therefore, we evaluated nervous system disease in feline MLII. MLII cats lived to approximately 5 months of age, had impairments in hearing and sensory nerve conduction, hydrocephalus, and increased expression of lysosomal associated membrane protein 1. Quantification of cytokines and chemokines revealed dysregulation, elucidating potential pathomechanisms and non-invasive biomarkers. We then evaluated adeno-associated virus (AAV)-mediated gene therapy. MLII cats were treated with AAV9 encoding feline GNPTAB. High-dose AAV9-fGNPTAB intervention in the first week of life was fatal; however, delaying treatment to 4 weeks was tolerated. Correction was not complete, however, the highest dose resulted in the greatest correction of ophthalmic, skeletal, and cardiac disease associated with MLII.
2024-12-11 | Atp6v0d2 deficiency partially restores defects in Mcoln1-deficient mouse corpus luteum
Objective: ATP6V0d2 is a subunit of the vacuolar-type H + -ATPase (V-ATPase) that pumps H + ions into lysosomes. TRPML1 ( MCOLN1 / Mcoln1 ) transports cations out of lysosomes. Mcoln1 −/− mice recapitulate the lysosomal storage disorder mucolipidosis type IV (MLIV) phenotype. We previously demonstrated that Mcoln1 −/− female mice quickly became infertile at 5 months old (5M) with degenerating corpora lutea (CL) and progesterone (P4) deficiency. We tested our hypothesis that Atp6v0d2 deficiency could partially compensate for Mcoln1 deficiency to restore CL functions in Atp6v0d2 −/− Mcoln1 −/− mice. Methods: Control and Atp6v0d2 −/− Mcoln1 −/− female mice underwent fertility test from 2M to 7M old. A subset of them was dissected at 5M on day 3.5 post-coitum (D3.5). The D3.5 ovaries from 5M old control, Mcoln1 −/− , and Atp6v0d2 −/− Mcoln1 −/− mice were evaluated for CL morphology, lipid droplet staining, and markers of mitochondria and P4 steroidogenesis in the luteal cells. Results: The fertility test of Atp6v0d2 −/− Mcoln1 −/− female mice (2M–7M) revealed normal mating activity but reduced fertility compared with the control; yet ~25% of them remained fertile at 5–7M but with dystocia. We analyzed a subset of 11 Atp6v0d2 −/− Mcoln1 −/− mice (5M old) in the fertility test on D3.5: three (27.3%) had normal P4 levels and all examined CL parameters, indicating fully restoration of CL function compare with Mcoln1 −/−; whereas eight had P4 deficiency, with two (18.2%) infertile and six (54.5%) once fertile. In contrast to Mcoln1 −/− CLs, which had extensive amorphous cellular debris, indicating cell degeneration, Atp6v0d2 −/− Mcoln1 −/− CLs had reduced amorphous cellular debris regardless of P4 levels. However, similar to Mcoln1 −/− CLs, P4-deficient Atp6v0d2 −/− Mcoln1 −/− CLs showed impaired differentiation, enlarged lipid droplets, disorganized expression of endothelial basal lamina marker collagen IV, and reduced expression of mitochondrial marker HSP60 and steroidogenesis rate-limiting protein StAR, indicating that additional Atp6v0d2 deficiency compensates for Mcoln1 deficiency-induced cell degeneration, but is insufficient to restore luteal cell differentiation and P4 steroidogenesis in P4-deficient Atp6v0d2 −/− Mcoln1 −/− CLs. Conclusion: This study shows that Atp6v0d2 −/− Mcoln1 −/− CLs had varied improvements compared with Mcoln1 −/− CLs, and it provides in vivo genetic evidence of the coordination between different lysosomal channels in CL function.
2024-12-04 | TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.
Loss of function mutations in the lysosomal channel TRPML-1 cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood. A cross-sectional review of medical records from 21 MLIV patients (ages 3-43 years) was conducted to assess kidney function impairment. Additionally, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo renal filtration measurements. Of the 21 MLIV patients only adults were diagnosed with stage 2-3 chronic kidney disease. Laboratory abnormalities included decreased eGFR, higher levels BUN/Creatine in bloodand proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor-mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. Additionally, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the pro-inflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, AAV-mediated TRPML-1 gene delivery reversed key pathological phenotypes in Mucolipidosis type IV mice, underscoring TRPML-1's critical role in kidney function. Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV, providing new insights into its pathogenesis and potential therapeutic targets.
other
2026-06-18 | Relevance of functional studies for assessing an antisense oligonucleotide-mediated exon skipping therapeutic strategy for mucolipidosis type II.
Mucolipidosis type II (ML II) is a lysosomal storage disorder caused by deficiency of N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), which impairs the trafficking of lysosomal hydrolases. Of all ML II pathogenic variants, c.3503_3504del in GNPTAB exon 19 is the most prevalent, therefore constituting a compelling molecular target for the development of personalized therapeutic strategies. Here, we explored the feasibility of an innovative RNA based-therapeutic strategy using antisense oligonucleotides (ASOs) designed to induce exon 19 skipping in GNPTAB pre-mRNA. This approach was previously successfully tested at the mRNA level in fibroblasts from ML II patients, where it generated an in-frame mRNA. In the present study, our aim was to evaluate whether GNPTAB exon 19 skipping could increase GlcNAc-PT levels and consequently improve the cellular phenotype of ML II patients carrying this pathogenic variant. To address this, we designed a functional approach based on the overexpression of a GNPTAB construct carrying the exon 19 deletion enabling the indirect evaluation of the resulting protein´s functionality. Our first results demonstrated that in ML II fibroblasts, ASO treatment led to a modest increase in lysosomal hydrolase activity at 24 h and 48 h. Moreover, LAMP-1 expression remained elevated and comparable to untreated ML II cells, indicating that GlcNAc-PT activity was not restored. To further investigate the functional relevance of exon 19 skipping, overexpression studies were performed in HEK293T cells. Three constructs (pGNPTAB WT, pGNPTAB del_exon19 and pGNPTAB c.3503_3504del) were expressed. Both pGNPTAB WT and pGNPTAB del_exon19 constructs produced the α/β-precursor. However, only the WT construct generated the mature β-subunit, whereas the pGNPTAB c.3503_3504del construct showed no detectable expression. These findings indicate that exon 19 is essential for proper GlcNAc-PT processing and enzymatic activity. Although ASO treatment corrected splicing at the mRNA level, it did not restore GlcNAc-PT activity in ML II patient cells. Nonetheless, our findings clarify the functional importance of exon 19 and demonstrate that overexpression of an exon-skipped construct provides a simple and effective strategy to indirectly assess protein functionality, supporting the prioritization of this kind of approach to test an exon-skipping ASO-based approach before advancing to studies in patient-derived cells.
2025-02-12 | LYSET facilitates integration of both the N- and C-terminal transmembrane helices/cytoplasmic domains of GlcNAc-1-phosphotransferase.
LYSET is a recently identified Golgi transmembrane (TM) protein, and inactivating mutations in the LYSET gene phenocopy mucolipidosis II (MLII), the lysosomal storage disease caused by loss of function of GlcNAc-1-phosphotransferase αβ (GNPTαβ), which tags lysosomal hydrolases with the mannose 6-phosphate (M6P) tag for delivery to lysosomes. It is conceivable that LYSET facilitates integration of both hydrophilic TM helices (TMHs) of GNPTαβ and retain the latter in the Golgi, although this has only been directly demonstrated for the N-terminal TMH wherein a membrane-stabilized GNPTαβ variant restores lysosomal function in cells lacking LYSET. Here we show that the C-terminal TMH of GNPTαβ also contributes to LYSET-mediated Golgi retention. In addition, disease-causing patient mutations in the N-terminal TMH of GNPTαβ, which increase the hydrophilicity of the helix, are partly rescued by overexpression of LYSET. Finally, we show that a membrane-stabilized GNPTαβ variant, despite overcoming the requirement for LYSET, still requires COPI-mediated recycling via the N-terminal cytosolic domain (CD) for GNPTαβ retention and function in the Golgi.
2021-08-23 | Development of an Antisense Oligonucleotide-Mediated Exon Skipping Therapeutic Strategy for Mucolipidosis II: Validation at RNA Level.
Lysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases caused by the malfunction of the lysosomal system, which results in the accumulation of undergraded substrates inside the lysosomes and leads to severe and progressive pathology. Despite there currently being a broad understanding of the molecular defects behind LSDs, curative therapies have been approved for only few of these diseases, whereas existing treatments are still mostly symptomatic with several limitations. Mucolipidosis type II alpha/beta (ML II) is one of most severe LSDs, which is caused by the total deficiency of the GlcNAc-1-phosphotransferase, a key enzyme for the formation of specific targeting signals on lysosomal hydrolases to lysosomes. GlcNAc-1-phosphotransferase is a multimeric enzyme complex encoded by two genes: GNPTAB and GNPTG. One of the most frequent ML II causal mutation is a dinucleotide deletion on exon 19 of GNPTAB (c.3503_3504del) that leads to the generation of a truncated protein, loss of GlcNAc-1-phosphotransferase activity, and missorting of multiple lysosomal enzymes. Presently, there is no therapy available for ML II. In this study, we explored the possibility of an innovative therapeutic strategy for ML II based on the use of antisense oligonucleotides (AOs) capable to induce the skipping of GNPTAB exon 19 harboring the most common disease-causing mutation, c.3503_3504del. The approach confirmed the ability of specific AOs for RNA splicing modulation, thus paving the way for future studies on the therapeutic potential of this strategy.
2015-04-15 | Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition.
UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. GNPTAB encodes the α and β subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III αβ. Prior investigation of missense mutations in GNPTAB uncovered amino acids in the N-terminal region and within the DMAP domain involved in Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases, respectively. Here, we undertook a comprehensive analysis of the remaining missense mutations in GNPTAB reported in mucolipidosis II and III αβ patients using cell- and zebrafish-based approaches. We show that the Stealth domain harbors the catalytic site, as some mutations in these regions greatly impaired the activity of the enzyme without affecting its Golgi localization and proteolytic processing. We also demonstrate a role for the Notch repeat 1 in lysosomal hydrolase recognition, as missense mutations in conserved cysteine residues in this domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases. Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. Finally, the mutant R587P, located in the spacer between Notch 2 and DMAP, was partially rescued by overexpression of the γ subunit, suggesting a role for this region in γ subunit binding. These studies provide new insight into the functions of the different domains of the α and β subunits.
2013-02-01 | Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter
Zinc is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular zinc is controlled by zinc-chelating proteins and by zinc transporters. The recent identification of zinc permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal zinc levels in cells deficient in TRPML1, suggested a role for TRPML1 in zinc transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and zinc staining, when cells are exposed to high concentrations of zinc. We now show that lysosomal enlargement and zinc build-up in TRPML1-KD cells exposed to zinc are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the zinc transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic zinc and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay zinc leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in zinc metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate zinc translocation between the cytoplasm and lysosomes.
proteins
2026-08-05 | Clinical phenotype and GNPTAB gene mutation spectrum analysis of Chinese patients with mucolipidosis type II α/β.
Mucolipidosis type II α/β (ML II α/β) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the GNPTAB gene, leading to GlcNAc-1-phosphotransferase deficiency and subsequent accumulation of intracellular toxic substances. This study aimed to systematically describe the clinical spectrum and mutational characteristics of Chinese patients with ML II α/β to facilitate early diagnosis and provide ethnicity-specific data. Whole-exome sequencing (WES) was performed on a new proband, and a comprehensive literature review was conducted, summarizing a total of 56 Chinese cases (including 1 new case). All patients presented with skeletal deformities (100%), 96.4% had coarse facial features, 94.6% had developmental delay, and the median age at diagnosis was 17.5 months. The new proband carried compound heterozygous non-sense mutations NM_024312.4:c.2455G>T (p.Glu819*) and NM_024312.4:c.1123C>T (p.Arg375*) and died of respiratory failure at 27 months of age. Notably, NM_024312.4:c.1090C>T (p.Arg364*) was the most common mutation (found in 39.3% of patients), associated with typical skeletal abnormalities and early death. Cardiac abnormalities (16.1%) and pulmonary complications (12.5%) were common comorbidities. This study identified a unique mutational hotspot in Chinese patients with ML II α/β and revealed a severe phenotype with poor prognosis, primarily resulting in death from respiratory failure. These findings are beneficial for clinical diagnosis, genetic counseling, and targeted molecular screening of this disease.
2026-03-17 | Isolated cardiac mucolipidosis type III α/β mimicking Fabry’s disease: a case report highlighting the role of pathology and genetics in diagnosis
A 39-year-old female presented with left precordial pain and chest tightness following emotional stress approximately 10 years ago. Initial coronary angiography was unremarkable, though electrocardiogram revealed mild ST-T changes (Panel A). Over the past year, the symptoms became more frequent with reduced tolerance of physical activity, accompanied by mild elevation in cardiac troponin I (0.217–0.227 ng/mL, normal < 0.04) and T-wave inversion (Panel B). Cardiac magnetic resonance imaging revealed normal structure on cine four-chamber images (Panel C) and no late gadolinium enhancement (Panel D). Endomyocardial biopsy revealed extensive vacuolar degeneration under light microscopy (Panel E), loss of galactosidase expression on immunohistochemistry (Panel F), and myelin-like bodies accumulation under electron microscopy (Panel G). Fabry’s disease was suspected, but GLA gene sequencing and lyso-globotriaosylsphingosine came back negative. Whole-exome sequencing identified a pathogenic mutation (c.2715+1G>A) and a variant of uncertain significance (c.1702T>G) in GNPTAB gene. Elevated plasma lysosomal enzyme levels confirmed mucolipidosis (ML) type III α/β. Physical examination showed no skeletal abnormalities or characteristic facial features. The patient was diagnosed with MLIII α/β with early cardiomyopathy and managed supportively, with close cardiac monitoring for early signs of heart failure.
2025-11-20 | Differential ion selectivity and disease-associated dysfunction of TRPML channels revealed by patient and engineered mutants.
The endolysosomal transient receptor potential mucolipin (TRPML) channels play key roles in regulating lysosomal trafficking, signaling, and function. While mutations in TRPML1 cause mucolipidosis type IV (MLIV), the functional consequences of many disease-associated mutations remain unclear. In this study, we used live-cell confocal imaging in HeLa cells to comprehensively characterize the subcellular localization and cation (Ca2+ and Zn2+) permeability of TRPML1-3, 10 TRPML1 MLIV patient-derived mutants, and engineered pore mutants. We showed that TRPML1 and TRPML3 permeate both Ca2+ and Zn2+, whereas TRPML2 conducts only Ca2+. Subcellular localization analyses revealed that TRPML1 and TRPML2 localize predominantly to lysosomes, whereas TRPML3 is preferentially localized to the endoplasmic reticulum. Among the 10 patient-derived TRPML1 mutants, nine exhibited severely impaired agonist-mediated Ca2+ and Zn2+ permeability, indicating severe functional loss. In contrast, the F408Δ mutant, associated with a milder phenotype, retained partial ion permeability and was the only mutant capable of constitutive Ca2+ permeation without agonist stimulation. Interestingly, we found that nonfunctional, lysosome-localized TRPML1 mutants are associated with more severe disease phenotypes than those retained in the endoplasmic reticulum, suggesting that lysosomal localization of nonfunctional TRPML1 may have dominant-negative or toxic effects. Finally, through structure-guided mutagenesis, we generated a metal-selective TRPML1 mutant, I468V, that is permeable to Ca2+ but not to Zn2+, providing a new tool for dissecting the distinct physiological roles of Zn2+ and Ca2+ in TRPML1-mediated processes. Together, these findings provide new insights into how TRPML1 mutations disrupt subcellular localization, ion permeability, and selectivity, which contribute to the variable clinical spectrum of MLIV.
2025-06-09 | Exploring human plasma proteomic variations in mucolipidosis type IV.
Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.
2024-11-18 | Physiological and Pathological Functions of TRPML1
The lysosome is a nutrient recycling center and a sophisticated cellular signaling hub in the cell. It governs various cellular processes, including endocytosis, phagocytosis, and autophagy. Lysosomal dysfunction has been linked to a variety of human pathological conditions. The functions of lysosomes are controlled by not only digestive enzymes but also ion channels and ion transporters, a group of transmembrane proteins residing in the membrane of lysosomes. Among these ion channels and ion transporters, the transient receptor potential mucolipin 1 (TRPML1) channel is the major Ca2+-permeable channel that plays an important role in lysosome physiology. Mutations in TRPML1 have been associated with mucolipidosis type IV (ML-IV) disease. TRPML1 dysfunction has also been implicated in multiple pathological conditions. In this chapter, we will summarize and discuss the diverse functions of TRPML1 in lysosomes and other cellular processes under both physiological and pathological conditions.
small molecules
2026-06-20 | Zoledronic acid ameliorates multiple organ pathologies in a murine model of mucolipidosis II by partially restoring mannose-6-phosphate-mediated lysosomal hydrolase activities.
Mucolipidosis II (MLII) is a severe lysosomal disorder caused by loss of GlcNAc-1-phosphotransferase activity, leading to defective mannose-6-phosphate (M6P) tagging and subsequently misrouting of M6P-dependent lysosomal hydrolases, and progressive multi-organ pathology. We generated a Gnptab p.R364X knock-in mouse model of MLII, which recapitulated the biochemical, skeletal, visceral, and neurological features of human MLII. Proteomic analysis of lysosomes isolated from MLII fibroblasts by LysoIP showed depletion or decrease of M6P-dependent hydrolases, upregulation of M6P-independent enzymes, and increased abundance of lysosomal membrane proteins. Zoledronic acid treatment increased both M6P-dependent and M6P-independent luminal hydrolases, and reduced glycosaminoglycan storage in MLII skin fibroblasts. Besides skeletal density improvement, Zoledronic acid, administered from 4 to 24 weeks to MLII mice, ameliorated multiple system manifestations, including articular cartilage degeneration, motor impairment, hepatomegaly, along with decreased urinary heparan sulfate and brain neuroinflammation. Our findings demonstrate that zoledronic acid ameliorates multiple system pathologies in MLII mice, which may be mediated, at least in part, through partial restoration of M6P-dependent proteins within lysosomes.
2026-05-03 | Peroxisome-derived ether lipids regulate lysosomal exocytosis.
Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.
2026-01-01 | TRPML1 suppresses pulmonary fibrosis by limiting collagen and elastin deposition
In pulmonary fibrosis lung tissue is thickened and scarred, and the lungs become progressively stiffer and smaller, leading to low levels of blood oxygen and shortness of breath. Lung fibrosis is not curable and life expectancy is reduced. Fibrosis is characterized by an increased accumulation of extracellular matrix (ECM) proteins such as collagen and elastin. ECM proteins are degraded predominantly by matrix metalloproteinases (MMPs). Here, we show that the lysosomal cation channel TRPML1, which causes the lysosomal storage disorder mucolipidosis type IV (MLIV) when mutated or lost, regulates the levels of MMPs in the ECM of mouse airways, modulating exocytosis of MMP2, 8, 9, 12, and 19, which mediate collagen/elastin degradation. While TRPML1 loss reduces MMP levels in lung macrophage and fibroblast supernatants, small molecule activation of TRPML1 results in increased levels. MLIV mice display a fibrosis-like lung phenotype similar to the phenotype evoked by bleomycin. We thus identify TRPML1 as a regulator of MMP release in the lung with loss of TRPML1 resulting in lung fibrosis due to excessive extracellular collagen and elastin accumulation.
2025-05-07 | Disruption of Man-6-P-Dependent Sorting to Lysosomes Confers IGF1R-Mediated Apoptosis Resistance.
Mutations in GNPTAB underlie mucolipidosis II and mucolipidosis III α/β, which are inherited lysosomal storage disorders caused by a defective UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine phosphotransferase. As a result, newly synthesized acid hydrolases fail to acquire Mannose-6-Phosphate (Man-6-P) sorting signals, or do so to a lesser extent, and exhibit an impaired trafficking to lysosomes. Interestingly, we found that GNPTAB knockout HeLa cells are resistant to several cytotoxic agents: doxorubicin, chloroquine, staurosporine and paclitaxel. While we detected an increased trapping of weak bases in the expanded lysosomal population of these cells, which could reduce the effect of doxorubicin and chloroquine; the decreased cell response to staurosporine and paclitaxel suggested the involvement of alternative resistance mechanisms. Indeed, further investigation revealed that the hyperactivation of the Insulin-like Growth Factor 1 Receptor (IGF1R) pathway is a central player in the apoptosis resistance exhibited by Man-6-P sorting deficient cells.
2025-02-19 | TPC2 in drug development: Emerging target for cancer, viral infections, cardiovascular diseases, and neurological disorders
The lysosomal two-pore channel 2 (TPC2) modulates intracellular calcium (Ca 2 + ) signaling and has been implicated in inflammatory, cardiovascular, and neurodegenerative conditions, as well as cancer and viral infections. Despite its potential as a drug target, TPC2 is still in the early stages of therapeutic development. The major challenges include achieving high target specificity without inducing unintended effects on other endolysosomal channels and on the crosstalk between TPC2 and other intracellular and extracellular Ca 2+ channels. Recent advancements in the structural analysis of TPC2, along with the development of TPC2 agonists and inhibitors, have significantly expanded our understanding of its mechanistic contributions to disease. This review highlights potential TPC2-based therapies for cancer, inflammation, and neurological disorders, emphasizing the need for further research to develop targeted TPC2 modulators and fully elucidate the molecular mechanisms of TPC2. • TPC2 modulates angiogenesis, proliferation, and metastasis, positioning it as a potential therapeutic target in oncology. • Dysregulated TPC2 signaling is implicated in lysosomal storage disorders, including Type IV mucolipidosis, underscoring its therapeutic relevance. • Future research aims to enhance TPC2 modulator specificity, elucidate its role in Ca²⁺ signaling crosstalk, and address context-dependent effects for translational applications.
cell therapies
2026-01-06 | Failure of Allogeneic Transplant to Correct Sialidosis Despite Early Diagnosis and Full Donor Engraftment of Non-Carrier Leucocytes.
Sialidosis, also known as Mucolipidosis Type I, is a rare condition caused by defects in the NEU1 gene which causes the accumulation of sialylated peptides, oligosaccharides, and glycoproteins leading to neurological decline. Haematopoetic stem cell transplantation has been performed in the symptomatic phase twice in the literature but has failed to prevent deterioration. We report on a case where a 4-year-old child was diagnosed with pre-symptomatic sialidosis due to investigation following the incidental detection of a cherry-red spot prior to the onset of neurological symptoms. We performed haematopoetic stem cell transplantation with a matched unrelated cord blood unit with optimal timing prior to clinical decline, achieving full donor engraftment with a largely uneventful post-transplant recovery followed by a period of relative clinical stability. However, subsequent neurological decline detailed by clinical history and radiological findings has occurred suggesting a lack of disease responsiveness to transplantation despite optimal timing. We go on to provide supporting laboratory investigations detailing sialidosis fibroblast culture as part of a novel cross-correction assay and compare results to other transplant responsive lysosomal storage disorders such as mucopolysaccharidosis type 1-H and detail a lack of cross-correction in concordance with our clinical findings. We conclude that conventional allogeneic haematopoetic stem cell transplantation is not a viable disease-modifying treatment option in sialidosis, even when performed optimally in the pre-symptomatic phase, and suggest that alternative treatment options must be explored to improve outcomes in this condition.
2025-09-26 | A Rare Case Report OF A Newborn That May Be Confused With Rickets Aad Other Metabolic Bone Dısorders: I-Cell Disease
I cell disease (Mucolipidosis II) is a rare autosomal recessive lysosomal storage disease characterised by severe skeletal abnormalities, intrauterine growth retardation, coarse facial appearance, progressive psychomotor retardation, thickening of the skin, gingival hyperplasia, hernias and early death. It is caused by a deficiency of N-acetylglucosamine 1-phosphotransferase which is normally found in the endoplasmic reticulum or Golgi apparatus. Since the clinical, biochemical and laboratory findings of the disease mimic rickets, the diagnosis may be difficult at the beginning
2024-12-23 | Clinical and molecular characteristics of 20 Chinese probands with Mucolipidosis type II and III alpha/beta.
Mucolipidosis (ML) II and III alpha/beta are lysosomal disorders caused by mutations in the GNPTAB gene which encodes the alpha and beta subunits of the heterohexameric enzyme, N-acetylglucosamine-1-phosphotransferase. To explore the clinical and molecular characteristics of the 20 ML II and III alpha/beta patients, clinical data was collected and GNPTAB gene was analyzed by nest PCR and direct Sanger-sequencing. The activity of several lysosomal enzymes was measured in the plasma. Among the 20 ML II and III alpha/beta patients, 6 patients were classified as ML II and 14 as ML III alpha/beta. The main clinical manifestations were joint stiffness, skeletal deformity, mental retardation and short stature. Bone X-ray examination showed radiological changes. The plasma arylsulfatase A and hexosaminidase A enzyme activities increased significantly. Urinary glycosaminoglycan values were normal. We detected mutations in GNPTAB in 35 of 40 alleles (87.5%). Mutation c.2715 + 1G > A and c.2404 C > T (p.Gln802Ter) were the most prevalent variants, accounting for 14.3% and 11.4%, respectively. Five novel mutations c.3335 + 5G > A, c.1284 + 1G > A, c.571 + 4 A > G, c.1634_1635delAA (p.Lys545Serfs*16) and c.1582T > C(p.Cys528Arg) were identified. Our study expands the spectrum of GNPTAB gene in China. Mutation c.2715 + 1G > A was the most prevalent mutation in our study. The novel mutation c.1284 + 1G > A might be a severe mutation associated with ML II.
2023-07-06 | Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations
Mucolipidosis type II (MLII), or I-cell disease, is a rare lysosomal storage disease (LSD) caused by variants in the GNPTAB gene. MLII patients exhibit clinical phenotypes in the prenatal or neonatal stage, such as marked dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, and mental and motor developmental abnormalities. The median age at diagnosis for MLII is 0.7 years, the median survival is 5.0 years, and the median age at death is 1.8 years. No cure for MLII exists.Sanger sequencing of the GNPTAB gene identified the compound heterozygous mutations c.673C > T in exon 7 and c.1090C > T in exon 9, which were novel double heterozygous mutations first reported in China. For the first time, we describe our experience in the use of HSCT for MLII. Our patient underwent HSCT with cells from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor at 12 months of age. Myeloid neutrophil and platelet engraftment occurred on Days 10 and 11, respectively.The patient's limb muscle tension was significantly reduced, and his gross and fine motor skills were improved four months after transplantation. DST(Developmental Screen Test) results showed that the patient's fine motor skills and mental development were improved compared with before HSCT.MLII is a very severe lysosomal storage disease, to date, only 3 cases have been reported on the use of HSCT to treat MLII. Our data show that HSCT is a potential way to prolong the life of patients and improve their quality of life. Due to the lack of comparable data and time, the exact benefit remains unclear in MLII patients. Longer-term follow-up and in-depth prospective studies are indispensable.
2021-03-05 | The Role of Hematopoietic Cell Transplant in the Glycoprotein Diseases.
The glycoprotein disorders are a group of lysosomal storage diseases (α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, sialidosis, mucolipidosis II, mucolipidosis III, and Schindler Disease) characterized by specific lysosomal enzyme defects and resultant buildup of undegraded glycoprotein substrates. This buildup causes a multitude of abnormalities in patients including skeletal dysplasia, inflammation, ocular abnormalities, liver and spleen enlargement, myoclonus, ataxia, psychomotor delay, and mild to severe neurodegeneration. Pharmacological treatment options exist through enzyme replacement therapy (ERT) for a few, but therapies for this group of disorders is largely lacking. Hematopoietic cell transplant (HCT) has been explored as a potential therapeutic option for many of these disorders, as HCT introduces functional enzyme-producing cells into the bone marrow and blood along with the engraftment of healthy donor cells in the central nervous system (presumably as brain macrophages or a type of microglial cell). The outcome of HCT varies widely by disease type. We report our institutional experience with HCT as well as a review of the literature to better understand HCT and outcomes for the glycoprotein disorders.
gene therapies
2026-01-22 | Pneumothorax as a life‐threatening long‐term complication with mucolipidosis type II
The authors declare no conflicts of interest. The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Table S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2025-06-20 | Neuraminidase 1 secondary deficiency contributes to CNS pathology in neurological mucopolysaccharidoses via brain protein hypersialylation.
Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III, and VII, which are associated with lysosomal accumulation of heparan sulphate (HS), manifest with neurological deterioration and currently lack effective treatments. We report that neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of patients with neurological MPS and mouse models but not in neurological lysosomal disorders without HS storage. Accumulated HS disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A, β-galactosidase (GLB1), and glucosamine-6-sulfate sulfatase (GALNS), leading to NEU1 deficiency and partial GLB1 and GALNS deficiencies in cortical tissues and induced pluripotent stem cell-derived (iPSC-derived) cortical neurons of patients with neurological MPS. Increased sialylation of N-linked glycans in brains of patients with MPS and mice implicated insufficient processing of sialylated glycans, except for polysialic acid. Correction of NEU1 activity in MPS IIIC mice by lentiviral (LV) gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioral traits, and reduced levels of excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1/PSD95-positive puncta in cortical iPSC-derived MPS IIIA neurons. Our results demonstrate that HS-induced secondary NEU1 deficiency and aberrant sialylation of brain glycoproteins constitute what we believe is a novel pathological pathway in the neurological MPS spectrum crucially contributing to CNS pathology.
2025-04-26 | Age-sensitive response of systemic AAV-mediated gene therapy in a newly characterized feline model of mucolipidosis II.
Mucolipidosis II (MLII) is a lysosomal storage disorder (LSD) caused by mutations in GNPTAB and loss of mannose 6-phosphate-dependent targeting of lysosomal enzymes. Affected children exhibit cognitive deficits, skeletal dysplasia, and cardiopulmonary disease, with death typically occurring before age 10. A naturally occurring feline model of MLII results from a nonsense mutation in GNPTAB; cats develop elevated lysosomal enzyme activities, growth retardation, skeletal deformities, blindness, cardiomegaly, and die prematurely. Most LSDs exhibit central nervous system disease, which is a primary contributor to morbidity and mortality. Therefore, we evaluated nervous system disease in feline MLII. MLII cats lived to approximately 5 months of age, had impairments in hearing and sensory nerve conduction, hydrocephalus, and increased expression of lysosomal associated membrane protein 1. Quantification of cytokines and chemokines revealed dysregulation, elucidating potential pathomechanisms and non-invasive biomarkers. We then evaluated adeno-associated virus (AAV)-mediated gene therapy. MLII cats were treated with AAV9 encoding feline GNPTAB. High-dose AAV9-fGNPTAB intervention in the first week of life was fatal; however, delaying treatment to 4 weeks was tolerated. Correction was not complete, however, the highest dose resulted in the greatest correction of ophthalmic, skeletal, and cardiac disease associated with MLII.
2024-12-11 | Atp6v0d2 deficiency partially restores defects in Mcoln1-deficient mouse corpus luteum
Objective: ATP6V0d2 is a subunit of the vacuolar-type H + -ATPase (V-ATPase) that pumps H + ions into lysosomes. TRPML1 ( MCOLN1 / Mcoln1 ) transports cations out of lysosomes. Mcoln1 −/− mice recapitulate the lysosomal storage disorder mucolipidosis type IV (MLIV) phenotype. We previously demonstrated that Mcoln1 −/− female mice quickly became infertile at 5 months old (5M) with degenerating corpora lutea (CL) and progesterone (P4) deficiency. We tested our hypothesis that Atp6v0d2 deficiency could partially compensate for Mcoln1 deficiency to restore CL functions in Atp6v0d2 −/− Mcoln1 −/− mice. Methods: Control and Atp6v0d2 −/− Mcoln1 −/− female mice underwent fertility test from 2M to 7M old. A subset of them was dissected at 5M on day 3.5 post-coitum (D3.5). The D3.5 ovaries from 5M old control, Mcoln1 −/− , and Atp6v0d2 −/− Mcoln1 −/− mice were evaluated for CL morphology, lipid droplet staining, and markers of mitochondria and P4 steroidogenesis in the luteal cells. Results: The fertility test of Atp6v0d2 −/− Mcoln1 −/− female mice (2M–7M) revealed normal mating activity but reduced fertility compared with the control; yet ~25% of them remained fertile at 5–7M but with dystocia. We analyzed a subset of 11 Atp6v0d2 −/− Mcoln1 −/− mice (5M old) in the fertility test on D3.5: three (27.3%) had normal P4 levels and all examined CL parameters, indicating fully restoration of CL function compare with Mcoln1 −/−; whereas eight had P4 deficiency, with two (18.2%) infertile and six (54.5%) once fertile. In contrast to Mcoln1 −/− CLs, which had extensive amorphous cellular debris, indicating cell degeneration, Atp6v0d2 −/− Mcoln1 −/− CLs had reduced amorphous cellular debris regardless of P4 levels. However, similar to Mcoln1 −/− CLs, P4-deficient Atp6v0d2 −/− Mcoln1 −/− CLs showed impaired differentiation, enlarged lipid droplets, disorganized expression of endothelial basal lamina marker collagen IV, and reduced expression of mitochondrial marker HSP60 and steroidogenesis rate-limiting protein StAR, indicating that additional Atp6v0d2 deficiency compensates for Mcoln1 deficiency-induced cell degeneration, but is insufficient to restore luteal cell differentiation and P4 steroidogenesis in P4-deficient Atp6v0d2 −/− Mcoln1 −/− CLs. Conclusion: This study shows that Atp6v0d2 −/− Mcoln1 −/− CLs had varied improvements compared with Mcoln1 −/− CLs, and it provides in vivo genetic evidence of the coordination between different lysosomal channels in CL function.
2024-12-04 | TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.
Loss of function mutations in the lysosomal channel TRPML-1 cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood. A cross-sectional review of medical records from 21 MLIV patients (ages 3-43 years) was conducted to assess kidney function impairment. Additionally, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo renal filtration measurements. Of the 21 MLIV patients only adults were diagnosed with stage 2-3 chronic kidney disease. Laboratory abnormalities included decreased eGFR, higher levels BUN/Creatine in bloodand proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor-mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. Additionally, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the pro-inflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, AAV-mediated TRPML-1 gene delivery reversed key pathological phenotypes in Mucolipidosis type IV mice, underscoring TRPML-1's critical role in kidney function. Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV, providing new insights into its pathogenesis and potential therapeutic targets.
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2026-06-18 | Relevance of functional studies for assessing an antisense oligonucleotide-mediated exon skipping therapeutic strategy for mucolipidosis type II.
Mucolipidosis type II (ML II) is a lysosomal storage disorder caused by deficiency of N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT), which impairs the trafficking of lysosomal hydrolases. Of all ML II pathogenic variants, c.3503_3504del in GNPTAB exon 19 is the most prevalent, therefore constituting a compelling molecular target for the development of personalized therapeutic strategies. Here, we explored the feasibility of an innovative RNA based-therapeutic strategy using antisense oligonucleotides (ASOs) designed to induce exon 19 skipping in GNPTAB pre-mRNA. This approach was previously successfully tested at the mRNA level in fibroblasts from ML II patients, where it generated an in-frame mRNA. In the present study, our aim was to evaluate whether GNPTAB exon 19 skipping could increase GlcNAc-PT levels and consequently improve the cellular phenotype of ML II patients carrying this pathogenic variant. To address this, we designed a functional approach based on the overexpression of a GNPTAB construct carrying the exon 19 deletion enabling the indirect evaluation of the resulting protein´s functionality. Our first results demonstrated that in ML II fibroblasts, ASO treatment led to a modest increase in lysosomal hydrolase activity at 24 h and 48 h. Moreover, LAMP-1 expression remained elevated and comparable to untreated ML II cells, indicating that GlcNAc-PT activity was not restored. To further investigate the functional relevance of exon 19 skipping, overexpression studies were performed in HEK293T cells. Three constructs (pGNPTAB WT, pGNPTAB del_exon19 and pGNPTAB c.3503_3504del) were expressed. Both pGNPTAB WT and pGNPTAB del_exon19 constructs produced the α/β-precursor. However, only the WT construct generated the mature β-subunit, whereas the pGNPTAB c.3503_3504del construct showed no detectable expression. These findings indicate that exon 19 is essential for proper GlcNAc-PT processing and enzymatic activity. Although ASO treatment corrected splicing at the mRNA level, it did not restore GlcNAc-PT activity in ML II patient cells. Nonetheless, our findings clarify the functional importance of exon 19 and demonstrate that overexpression of an exon-skipped construct provides a simple and effective strategy to indirectly assess protein functionality, supporting the prioritization of this kind of approach to test an exon-skipping ASO-based approach before advancing to studies in patient-derived cells.
2025-02-12 | LYSET facilitates integration of both the N- and C-terminal transmembrane helices/cytoplasmic domains of GlcNAc-1-phosphotransferase.
LYSET is a recently identified Golgi transmembrane (TM) protein, and inactivating mutations in the LYSET gene phenocopy mucolipidosis II (MLII), the lysosomal storage disease caused by loss of function of GlcNAc-1-phosphotransferase αβ (GNPTαβ), which tags lysosomal hydrolases with the mannose 6-phosphate (M6P) tag for delivery to lysosomes. It is conceivable that LYSET facilitates integration of both hydrophilic TM helices (TMHs) of GNPTαβ and retain the latter in the Golgi, although this has only been directly demonstrated for the N-terminal TMH wherein a membrane-stabilized GNPTαβ variant restores lysosomal function in cells lacking LYSET. Here we show that the C-terminal TMH of GNPTαβ also contributes to LYSET-mediated Golgi retention. In addition, disease-causing patient mutations in the N-terminal TMH of GNPTαβ, which increase the hydrophilicity of the helix, are partly rescued by overexpression of LYSET. Finally, we show that a membrane-stabilized GNPTαβ variant, despite overcoming the requirement for LYSET, still requires COPI-mediated recycling via the N-terminal cytosolic domain (CD) for GNPTαβ retention and function in the Golgi.
2021-08-23 | Development of an Antisense Oligonucleotide-Mediated Exon Skipping Therapeutic Strategy for Mucolipidosis II: Validation at RNA Level.
Lysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases caused by the malfunction of the lysosomal system, which results in the accumulation of undergraded substrates inside the lysosomes and leads to severe and progressive pathology. Despite there currently being a broad understanding of the molecular defects behind LSDs, curative therapies have been approved for only few of these diseases, whereas existing treatments are still mostly symptomatic with several limitations. Mucolipidosis type II alpha/beta (ML II) is one of most severe LSDs, which is caused by the total deficiency of the GlcNAc-1-phosphotransferase, a key enzyme for the formation of specific targeting signals on lysosomal hydrolases to lysosomes. GlcNAc-1-phosphotransferase is a multimeric enzyme complex encoded by two genes: GNPTAB and GNPTG. One of the most frequent ML II causal mutation is a dinucleotide deletion on exon 19 of GNPTAB (c.3503_3504del) that leads to the generation of a truncated protein, loss of GlcNAc-1-phosphotransferase activity, and missorting of multiple lysosomal enzymes. Presently, there is no therapy available for ML II. In this study, we explored the possibility of an innovative therapeutic strategy for ML II based on the use of antisense oligonucleotides (AOs) capable to induce the skipping of GNPTAB exon 19 harboring the most common disease-causing mutation, c.3503_3504del. The approach confirmed the ability of specific AOs for RNA splicing modulation, thus paving the way for future studies on the therapeutic potential of this strategy.
2015-04-15 | Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition.
UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. GNPTAB encodes the α and β subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III αβ. Prior investigation of missense mutations in GNPTAB uncovered amino acids in the N-terminal region and within the DMAP domain involved in Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases, respectively. Here, we undertook a comprehensive analysis of the remaining missense mutations in GNPTAB reported in mucolipidosis II and III αβ patients using cell- and zebrafish-based approaches. We show that the Stealth domain harbors the catalytic site, as some mutations in these regions greatly impaired the activity of the enzyme without affecting its Golgi localization and proteolytic processing. We also demonstrate a role for the Notch repeat 1 in lysosomal hydrolase recognition, as missense mutations in conserved cysteine residues in this domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases. Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. Finally, the mutant R587P, located in the spacer between Notch 2 and DMAP, was partially rescued by overexpression of the γ subunit, suggesting a role for this region in γ subunit binding. These studies provide new insight into the functions of the different domains of the α and β subunits.
2013-02-01 | Zinc-dependent lysosomal enlargement in TRPML1-deficient cells involves MTF-1 transcription factor and ZnT4 (Slc30a4) transporter
Zinc is critical for a multitude of cellular processes, including gene expression, secretion and enzymatic activities. Cellular zinc is controlled by zinc-chelating proteins and by zinc transporters. The recent identification of zinc permeability of the lysosomal ion channel TRPML1 (transient receptor potential mucolipin 1), and the evidence of abnormal zinc levels in cells deficient in TRPML1, suggested a role for TRPML1 in zinc transport. In the present study we provide new evidence for such a role and identify additional cellular components responsible for it. In agreement with the previously published data, an acute siRNA (small interfering RNA)-driven TRPML1 KD (knockdown) leads to the build-up of large cytoplasmic vesicles positive for LysoTracker™ and zinc staining, when cells are exposed to high concentrations of zinc. We now show that lysosomal enlargement and zinc build-up in TRPML1-KD cells exposed to zinc are ameliorated by KD of the zinc-sensitive transcription factor MTF-1 (metal-regulatory-element-binding transcription factor-1) or the zinc transporter ZnT4. TRPML1 KD is associated with a build-up of cytoplasmic zinc and with enhanced transcriptional response of mRNA for MT2a (metallothionein 2a). TRPML1 KD did not suppress lysosomal secretion, but it did delay zinc leak from the lysosomes into the cytoplasm. These results underscore a role for TRPML1 in zinc metabolism. Furthermore, they suggest that TRPML1 works in concert with ZnT4 to regulate zinc translocation between the cytoplasm and lysosomes.
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Drug Discovery Landscape
1 orphan drug designation for Mucolipidosis.
1 orphan drug designation for Mucolipidosis.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated viral vector type 9 with S1S3 gene encoding S1S3 variant of N-acetylglucosamine-1-phosphotransferase | gene therapies | FDA | 2020-10-20 | — | M6P Therapeutics |
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