RARE DISEASE
Oculocutaneous albinism
Oculocutaneous albinism
Oculocutaneous albinism
Synonyms: OCA
Synonyms: OCA
Synonyms: OCA
Drug discovery
280
papers
On emerging therapies
Overview
Oculocutaneous albinism (OCA) is a group of autosomal recessive genetic disorders caused by mutations in genes regulating melanin synthesis (e.g., TYR, OCA2), leading to reduced pigmentation in skin, hair, and eyes. Key clinical features include vision abnormalities (nystagmus, strabismus, photophobia, foveal hypoplasia) and heightened UV sensitivity, increasing skin cancer risk. Diagnosis relies on clinical evaluation, genetic testing, and ophthalmological assessment [1][6][14].
Therapies
Skin protection: Strict UV avoidance, high-SPF sunscreen, and dermatologic surveillance for malignancies [6][8][14].
Vision management: Corrective lenses, nystagmus/strabismus surgery, and low-vision aids [6][11][13].
Investigational therapies: Nitisinone (enhances tyrosine availability for OCA1B) and AAV-based gene therapy (preclinical success in animal models) [3][8][13].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare skin diseases
Research Papers
280 drug discovery papers about Oculocutaneous albinism, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
280 drug discovery papers about Oculocutaneous albinism, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-18 | Ampyrone is a direct agonist of human tyrosinase and a potential therapeutic for hypopigmentation disorders.
Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a human TYR construct, we developed high-throughput screening methods, in cell confirmatory assays employing 13C-tyrosine tracing, and computational analysis techniques, and identified ampyrone (4-aminoantipyrine) as a TYR activator. Ampyrone increased the in vitro catalytic activity of the human recombinant intra-melanosomal domain of TYR (hTYR) and its hypomorphic variant, Pro406Leu (P406L), a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, mouse OCA2 melanocytes, as well as 3-dimensional (3D) human skin cultures. Computational studies provided additional insight into the effects of direct TYR agonists on enzyme activity. Our results identified ampyrone as a lead candidate for TYR activation, potentially supporting the development of therapies for patients with genetic and acquired diseases of hypopigmentation.
2026-06-05 | Targeting melanosome pH is an effective method for the treatment of oculocutaneous albinism.
Oculocutaneous albinism (OCA) is a genetic condition associated with impaired visual acuity and increased skin cancer risk. When OCA is due to defects in melanosome ion transport, abnormally acidic conditions in the melanosome lumen inhibit tyrosinase, the critical pigment synthetic enzyme. Hence, a therapeutic approach that optimizes melanosome pH to increase pigment production presents a potential treatment for OCA and a method for decreasing skin cancer risk. Here, we report that reduction in sAC ( ADCY10 ) activity via naturally occurring human variants in ADCY10 restores OCA pigmentation, and sAC inhibition increases melanin synthesis in both human and mouse OCA models. These findings demonstrate that targeting melanosome pH is an effective, previously untapped therapeutic strategy for OCA and elevated skin cancer risk.
2026-02-07 | A Case Report on Oculocutaneous Albinism
Aims: Understanding the epidemiology, pathophysiology, clinical manifestations, causative mutations and management of oculocutaneous albinism by reporting a case of a 17 year old affected by this disease. Study Design: Case report: 17-year-old male presenting oculocutaneous albinism who presented for an ophthalmology consultation due to a profound decrease in visual acuity, associated with nystagmus and photophobia that had been progressing since early childhood. Discussion and Literature Review: We will comprehensively examine all aspects of oculocutaneous albinism by reviewing the literature on its epidemiology, pathophysiology, clinical manifestations, differential diagnosis, treatment, and prognosis. Conclusion: Advances in molecular diagnostics have significantly enhanced the detection of causative mutations, enabling improved clinical management and genetic counseling. Emerging therapeutic approaches, including pharmacological interventions, offer promising avenues for correcting pigmentation defects.
2025-12-25 | OCA2 deficiency enhances TPC2 channel activity to reduce melanosomal pH and pigment production.
Albinism is a heterogeneous inherited disorder with at least 21 known causative genes. Clinically, interpreting the potential digenic or oligogenic effects of the variants is a big challenge. We identified digenic mutations in a Chinese individual with oculocutaneous albinism, carrying a loss-of-function mutation in the Cl- (chloride) channel gene OCA2 (c.808-3C>G) and an unreported gain-of-function mutation in the Na+/Ca2+ channel gene TPCN2 (p.Ala24Val), which was confirmed by patch-clamp analysis. We further demonstrated that Cl- bilaterally modulated TPC2 activity by patch clamping: cytosolic high Cl- inhibited but luminal high Cl- enhanced TPC2 channel activity. Using CRISPR/Cas9-mediated knockout cell models and knockin mouse models, we confirmed that OCA2 modulated TPC2 activity by influencing melanosomal pH and pigment production. Mice mimicking double heterozygotes for the OCA2 loss-of-function p.Val443Ile and the TPCN2 gain-of-function p.Arg210Cys exhibited synergistic hypopigmentation in both fur and retina, phenocopying the albinism patient with digenic loss-of-function OCA2 and gain-of-function TPCN2 heterozygous mutations. This study provides experimental evidence supporting an oligogenic mode of inheritance in albinism, pinpoints melanosomal ion homeostasis as a key pathogenic mechanism and potential therapeutic target, and establishes a generalized research framework for elucidating gene-gene interactions in heterogeneous inherited disorders, especially for the channelopathies.
2025-12-10 | A Case Report on Oculocutaneous albinism
Aims: Understanding the epidemiology, pathophysiology, clinical manifestations, causative mutations and management of oculocutaneous albinism by reporting a case of a 7-year-old child affected by this disease Study Design: Case report. Case Report: 7-year-old child presenting oculocutaneous albinism who presented for an ophthalmology consultation due to a profound decrease in visual acuity, associated with nystagmus and photophobia that had been progressing since early childhood Discussion and Literature Review: We will comprehensively examine all aspects of oculocutaneous albinism by reviewing the literature on its epidemiology, pathophysiology, clinical manifestations, differential diagnosis, treatment, and prognosis. Conclusion: Advances in molecular diagnostics have significantly enhanced the detection of causative mutations, enabling improved clinical management and genetic counseling. Emerging therapeutic approaches, including pharmacological interventions, offer promising avenues for correcting pigmentation defects.
proteins
2026-09-24 | A novel TYR variant implicated in oculocutaneous albinism type 1 (OCA1): a study in an indigenous population in Southern Brazil.
Oculocutaneous albinism (OCA) is a genetic condition with an estimated global prevalence of 1 in 17,000, though this varies across populations. The Kaingang are a Brazilian Indigenous group belonging to the Macro-Jê language family. Report a novel variant TYR:c.704A>G; p.Tyr235Cys in homozygosity among individuals of Kaingang ethnicity in the state of Rio Grande do Sul, Brazil. A commercial next-generation sequencing (NGS-based) panel for hypopigmentation and oculocutaneous albinism was applied to one saliva sample; exome sequencing (ES) was performed using NGS in another individual; and the remaining 14 individuals were genotyped by quantitative real-time (qPCR). The detection of this variant in 14 individuals from the same Indigenous Territory, within an estimated population of 6,000, yields an allele frequency of 0.05, suggesting a founder effect in this population. The affected individuals were not closely related, suggesting that the recurrence of the variant is not due to recent consanguinity but rather to population structure and inheritance from a common ancestor. In addition, NGS and ES have proven essential for accurate diagnosis of oculocutaneous albinism and for molecular reclassification of cases previously diagnosed clinically. This study contributes to understanding the molecular profile of albinism in Brazilian Indigenous populations, sheds light on historically underrepresented communities in genetic research and has the potential to inform targeted interventions and public health policies for individuals with albinism in these communities.
2026-07-17 | The Role of SLC24A5 (NCKX5) in Human Skin Pigmentation: The Importance of Cation Transport Activity.
Human pigmentation is determined by melanosome development and melanin production through melanogenesis, a process regulated by melanogenic proteins. A single nucleotide polymorphism (A111T) in the SLC24A5 gene, which encodes the K⁺-dependent Na⁺/Ca2⁺ exchanger NCKX5, is a major determinant of normal variation in human skin and iris color. Despite the suggested role of NCKX5 in skin pigmentation, its ion transport function in melanogenesis remains unclear. To address this, we silenced SLC24A5 in pigmented human MNT1 melanoma cells using CRISPR/Cas9-mediated knockout. Loss of NCKX5 resulted in a marked reduction in eumelanin levels and the formation of abnormal, non-uniform melanosomes with defective fibrillar structure. To evaluate the functional role of NCKX5, we reconstituted depigmented cells with myc-tagged NCKX5 variants, including the transport-deficient mutant D383N. Reconstitution with the A111 variant of NCKX5 restored eumelanin synthesis more effectively than the T111 variant, whereas the D383N variant failed to rescue pigmentation. Moreover, the addition of the lysosomotropic weak base NH4Cl to the growth medium, which neutralizes the acidic pH of intracellular organelles, markedly increased eumelanin content in depigmented cells lacking NCKX5, suggesting a link between NCKX5-mediated Ca2+ transport activity in the TGN and melanosomal pH regulation. We also discuss the many NCKX5 mutants that have been reported to affect pigmentation in both humans (Oculocutaneous albinism or OCA6) and animals in the context of their potential effects on NCKX5-mediated Ca2+ transport activity.
2026-02-18 | A Dosage-Dependent Dominant-Negative Mechanism of SLC45A2(W74R) in Autosomal Dominant Oculocutaneous Albinism Revealed by Zebrafish Modeling.
To investigate the clinical characteristics of autosomal dominant oculocutaneous albinism (OCA) and functionally validate the heterozygous SLC45A2(W74R) variant using a zebrafish model. Three members of a Korean family with OCA underwent comprehensive clinical examinations. Targeted panel and genome sequencing were performed on the proband, and Sanger sequencing was performed on all affected family members. To assess the pathogenicity of the genetic variant, a slc45a2 knockout (KO) zebrafish model was generated using CRISPR technology. All three affected patients exhibited hair and iris hypopigmentation, with variable foveal hypoplasia and nystagmus. A heterozygous c.220T>C:p.(W74R) variant in SLC45A2 was identified and was absent in gnomAD v4.1. Multiple in silico predictions supported its pathogenicity (AlphaMissense: 0.993, CADD: 29.6, REVEL: 0.951). Genome sequencing revealed no additional pathogenic or common hypomorphic variants in other known OCA-related genes. The slc45a2 KO zebrafish exhibited a typical albino phenotype, which was rescued by melanocyte-specific expression of normal SLC45A2 but not by the SLC45A2(W74R) variant. Furthermore, the SLC45A2(W74R) variant suppressed pigmentation in heterozygous KO, but not in wild-type zebrafish, indicating a dominant-negative effect in a dosage-dependent manner. This study demonstrated that a heterozygous c.220T>C:p.(W74R) variant in SLC45A2 causes variable expressivity of OCA in a dominant inherited manner, and this variant interferes with melanogenesis in zebrafish. This study expands the mode of inheritance in OCA and provides crucial functional validation that is important for genetic counseling.
2026-01-20 | Co-option of Lysosomal Machinery for Biomineralization
Summary Biomineralization first emerged ∼600 million years ago, giving rise to novel strategies for buoyancy, locomotion, and defense. 1 Sponges are the only metazoans that build a silica-based skeleton, 2 and the cellular and molecular mechanisms underlying their silicification process are much less understood than in diatoms and land plants, the other two major biosilicifiers. Here, we show that the cells specialized for sponge biosilicification, termed sclerocytes, highly express lysosomal-associated genes, including the V-H + -ATPase (VHA) proton pump, oculocutaneous albinism type 2 (OCA2) anion channels, cathepsin-L proteins, silicateins, TMEM55A, TMEM192, TMEM199, and multiple other proteins involved with lysosomal maintenance and degradation. Further, we demonstrate that VHA protein localizes to the sclerocyte silica deposition vesicle (SDV) and that VHA-dependent SDV acidification is essential for silica spicule formation. This function mirrors the localization and role of VHA in diatom biosilicification, 3 while in land plants, acidification occurs extracellularly in the xylem and is driven by a different proton pump, the plasma membrane P-type H + -ATPase. 4,5 These results indicate that vesicle acidification is a shared mechanism for silica handling in sponges, diatoms, and plants. We also found that genes homologous to the plant silicon efflux transporter Lsi2, 6 which belong to the same gene family as OCA2, 7,8 are upregulated in sclerocytes. Using Hybridization Chain Reaction Fluorescence In Situ Hybridization (HCR-FISH), we found that sponge Lsi2 genes are expressed in sclerocytes, corroborating prior phylogenetic and transcriptomic evidence that Lsi2 homologs are involved in sponge and diatom silicic acid transport. 7–10 Taking into account previous work showing that VHA, cathepsins, and other lysosomal-associated genes have been associated with calcification across a remarkable range of eukaryotes including coccolitophores, 11 foraminifera, 12 sea urchins, 13 bryozoans, 14 crustaceans, 15 mollusks, 16 and mammals, 17 we posit that the various biomineralization mechanisms observed throughout the tree of life arose convergently through the co-option of an ancestral lysosomal gene toolkit.
2026-01-12 | First Report of Oculocutaneous Albinism Type I Among Baka Pygmies From Cameroon.
Oculocutaneous albinism type 1 (OCA1) caused by pathogenic variants of the TYR gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in skin, hair, and eyes. We had the opportunity to examine five East Cameroon Baka rainforest hunter-gatherers (historically called "Pygmies") with albinism and belonging to three different families. Screening of known albinism genes revealed a homozygous missense variant in the TYR gene, NM_000372.5: c.1109T>C; p.Met370Thr. In addition, one patient was also hemizygous for a variant in GPR143, the gene involved in ocular albinism (OA1). Another patient was also heterozygous for the common African and Afro-American 2.7-kb deletion in the OCA2 gene indicating admixture of one parent with neighboring Nzimé Bantu-speaking farmers. This is the first report of the occurrence of OCA1 in African rainforest hunter-gatherers.
gene therapies
2026-07-29 | Ocular Safety and Efficacy of AAV-mediated Tyrosinase Gene Augmentation in a Nonhuman Primate Model.
Oculocutaneous albinism type 1 (OCA1) is an inherited disorder caused by tyrosinase ( TYR ) gene mutations. Affected individuals experience visual impairment and severe photosensitivity from ocular hypomelanosis, with no current treatments. We evaluated the safety and efficacy of a TYR -encoding adeno-associated virus (AAV) vector in healthy rhesus macaques as a potential OCA1 treatment. A novel AAV2-based capsid (ATX002) was packaged with the human VMD2 promoter and TYR (h TYR ) fused with mGreenLantern (mGL). Two adult rhesus macaques were injected with ATX002-hVMD2-h TYR - mGL subretinally (OD) and intravitreally (OS). Safety and efficacy were assessed via comprehensive ophthalmic examination, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography at baseline and defined timepoints up to 12 weeks post-injection, followed by post-mortem immunohistochemistry (IHC). Both subretinal doses induced localized hypermelanosis by 3 weeks post-injection, which persisted through the study endpoint and was accompanied by measurable thickening of the retinal pigment epithelium (RPE) on SD-OCT. Histological IHC confirmed successful RPE transduction via robust mGL fluorescence, corroborating in vivo findings by revealing localized RPE hyperplasia and transgene-expressing cells adjacent to regions of de novo hypermelanosis. Intravitreal delivery did not induce any changes to the RPE. Transient uveitis was observed but successfully managed with anti-inflammatory treatment. Subretinal AAV- TYR delivery is a safe and effective approach with the potential to induce RPE pigmentation. These findings support the use of AAV- TYR gene therapy for OCA1, demonstrating efficacy and a manageable safety profile in a large-animal model, and provide a critical bridge toward human clinical translation.
2026-07-04 | Combining modeling approaches for rapid preclinical evaluation of retinal gene therapy
The pathway to developing genetic treatments for rare, monogenic ocular disorders has historically been impeded by limited options in preclinical testing pipelines. In this issue of Molecular Therapy Advances, Dr. Aman George and colleagues navigate this challenge by presenting a proof-of-principle investigation of an adeno-associated virus (AAV)-based gene therapy strategy for oculocutaneous albinism type 1A (OCA1A).1 Building on prior work2 using a constitutive promoter, their approach delivers a human TYROSINASE (TYR) transgene under the stringent transcriptional control of a human BESTROPHIN (VMD2) promoter to restore melanin synthesis.
2026-07-02 | Systemic, RPE-directed AAV- Tyrosinase therapy restores ocular pigmentation in an OCA1 mouse model
Abstract Oculocutaneous albinism type 1 (OCA1) is a pigmentation disorder caused by biallelic tyrosinase ( TYR ) mutations, an essential enzyme for melanin synthesis. TYR inactivity results in loss of hair, skin, and eye pigment, which is detrimental for ocular function. Hypopigmentation of iris, retinal pigment epithelium (RPE), and choroid results in severe photosensitivity and low visual acuity. There are currently no FDA-approved pigment restoring therapies for OCA1, making therapeutic development an unmet clinical need. To address this gap, we have advanced an adeno-associated viral (AAV)-mediated Tyr replacement approach for OCA1 ocular pigment restoration. We evaluated the optimal viral delivery strategy and vector cell-type specificity for iris, RPE, and choroid pigmentation in an OCA1 mouse model, testing intraocular and systemic viral delivery methods in conjunction with viral constructs of varying RPE-specificity. Early, systemic delivery of an RPE-directed AAV- Tyr construct, AAV9.2yf-VMD2- Tyr , achieved widespread ocular pigment rescue with minimal off-target expression in non-ocular tissues. Animals treated with AAV9.2yf-VMD2- Tyr demonstrated reduced photophobic behavior compared to untreated controls, indicating that ocular pigmentation restores a debilitating functional consequence of OCA1. Our findings establish a foundation for clinical translation of an AAV- TYR therapy aimed at improving light sensitivity, glare, and low vision through pigment restoration in patients with OCA1.
2026-05-15 | Gene therapy induces pigmentation in induced pluripotent stem cell-derived retinal pigment epithelium of OCA1A patients and albino rat eye.
Oculocutaneous albinism type 1A (OCA1A), the most severe and prevalent form of albinism, is caused by recessive mutations in the TYROSINASE gene. We provide proof-of-principle of an effective gene therapy-based strategy for future human application in OCA1A patients. Here, we show that an AAV-based TYROSINASE gene delivery under the control of human BESTROPHIN promoter VMD2 can successfully induce pigmentation in human retinal pigment epithelium (RPE) monolayer tissue, derived from OCA1A patients, via induced pluripotent stem cells. Pigmentation was induced without significantly compromising the RPE monolayer tissue integrity, apical-basal polarization, cellular morphology, or functionally relevant gene expression patterns. This human RPE-specific construct was able to induce pigmentation in albino rat RPE and choroid when delivered into eyes via suprachoroidal injection. Our strategy can be potentially employed to not only induce pigmentation but also efficiently deliver other target genes, without significantly compromising monolayer tissue integrity and viability of human RPE, a prime gene therapy target tissue for many degenerative disorders affecting vision.
2026-03-11 | Oculocutaneous albinism variants in 28 consanguineous families and functional classification of a pathogenic deep intron variant in TYR.
Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and molecular genetic diagnosis is important for classification of patients. Current diagnostic yield is approximately 70%, and a high proportion of patients are heterozygous for pathogenic variants in OCA genes, suggesting the presence of disease-causing non-coding variants. We describe here next generation sequencing (NGS) analysis, including copy number variant (CNV) analysis, of 28 consanguineous families, comprising a total of 136 individuals presenting with OCA. We provide a molecular genetic diagnosis in all 28 families. Noteworthy, five families (18%) had pathogenic variants in a gene associated with HPS, showing the importance of an in-depth molecular genetic investigation, which should be offered to persons with albinism. Furthermore, we report the first deep intron variant in TYR causing OCA and show by minigene analysis that the variant causes inclusion of a pseudoexon.
cell therapies
2025-05-19 | Hermansky-Pudlak Syndrome: From Molecular Pathogenesis to Targeted Therapies.
Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder caused by defects in lysosome-related organelles (LROs) in various tissues, including platelets, melanocytes, and endothelial cells. Key features of HPS include oculocutaneous albinism, bleeding tendency, and, in some cases, pulmonary fibrosis, granulomatous colitis, and immunodeficiency. The condition is linked to mutations in 11 genes involved in the formation of LROs. Currently, treatment options for HPS are limited and often ineffective. Though cell and gene therapies have been explored for melanosomes and epithelial cells, there is limited knowledge about their application to platelets and endothelial cells. Understanding the detailed mechanisms of HPS pathogenesis is crucial, and using induced pluripotent stem cell (iPSC) models may provide valuable insights into the disease's molecular processes, aiding the development of new treatments. In this review, we will focus on the genetics and molecular mechanisms of HPS, on its clinical manifestations and current therapeutic approaches, highlighting the need for further research into the disease mechanisms and potential innovative therapies.
2025-05-01 | Two in One: Bilateral Orthotopic Lung Transplant and Mitral Valve Replacement in a Case of Hermansky-Pudlak Syndrome
Abstract Intro: Hermanksy-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction, and, in severe forms, organ dysfunction manifest as colitis or pulmonary fibrosis (PF). Global prevalence estimates between 1-2 per million, but within select populations, such as Puerto Rico, prevalence is 1 in 1,800, constituting half of existing HPS cases. HPS subtypes 1, 2, and 4 have the highest incidence of PF due to lysosomal dysfunction and proliferative inflammatory response similar to IPF. Among Puerto Ricans with HPS, subtype 1 predominates, which has the highest incidence of PF. HPS pulmonary fibrosis (HPS-PF) has a gradual onset; however, our patient had a rapid progression to respiratory failure complicated by pulmonary hypertension (PH) and mitral regurgitation (MR) requiring complex medical and surgical management. Case: A pleasant 49-year-old Puerto Rican male with HPS presented with acute, progressive dyspnea in August. He was subsequently admitted to the ICU for acute hypoxic respiratory failure requiring BiPAP and was started on high dose steroids. With minimal improvement and persistent baseline 12-15L of O2 support, he was transferred to UNMC for transplant evaluation. CT chest revealed significant UIP/NSIP pattern of PF. Evaluation demonstrated moderate-severe MR and group 3 PH. Despite prolonged diuresis, treprostinil, and steroids, his oxygen requirements persisted. Multidisciplinary transplant evaluation was performed, and he was subsequently listed for lung transplant. In October, he deteriorated requiring continuous BiPAP until he succumbed to hypoxic bradycardia resulting in cardiac arrest with subsequent return of spontaneous circulation and cannulation for VV ECMO as bridge to lung transplant. Bilateral orthotopic lung transplant (BOLT) and simultaneous mitral valve repair occurred the following day. Postoperative course was complicated by prolonged ventilator wean necessitating tracheostomy; otherwise, the patient recovered as anticipated. Discussion: This case demonstrates the complex, multidisciplinary management required for HPS-PF. The patient's acute respiratory failure did not resolve with steroids leading to investigations of cardiac causes. Transthoracic echocardiogram revealed MR and elevated pulmonary artery systolic pressure. Further optimization of respiratory function included diuresis to euvolemia followed by right heart catheterization which demonstrated precapillary PH in the setting of PF. Treatment ensued with inhaled prostacyclin therapy in combination with diuretics. The question became the severity of mitral regurgitation and what its impact may be on lung transplant. Transesophageal echocardiogram performed perioperatively demonstrated severe MR necessitating complex valve replacement prior to BOLT. A novel feat allowing for successful lung transplant in HPS-PF.
2022-03-21 | In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium.
Oculocutaneous albinism (OCA) encompasses a set of autosomal recessive genetic conditions that affect pigmentation in the eye, skin, and hair. OCA patients display reduced best-corrected visual acuity, reduced to absent ocular pigmentation, abnormalities in fovea development, and/or abnormal decussation of optic nerve fibers. It has been hypothesized that improving eye pigmentation could prevent or rescue some of the vision defects. The goal of the present study was to develop an in vitro model for studying pigmentation defects in human retinal pigment epithelium (RPE). We developed a "disease in a dish" model for OCA1A and OCA2 types using induced pluripotent stem cells to generate RPE. The RPE is a monolayer of cells that are pigmented, polarized, and polygonal in shape, located between the neural retina and choroid, with an important role in vision. Here we show that RPE tissue derived in vitro from OCA patients recapitulates the pigmentation defects seen in albinism, while retaining the apical-basal polarity and normal polygonal morphology of the constituent RPE cells.
2019-08-30 | Chediak–Higashi syndrome: Lessons from a single-centre case series
Chediak–Higashi syndrome (CHS) is a rare and potentially fatal autosomal recessive disease characterized by frequent bacterial infections, bleeding tendency, oculocutaneous albinism, photosensitivity and progressive neurologic dysfunction. Owing to the rarity of this condition, the objective of this study was to describe patients with CHS. Retrospective evaluation of patients followed in a paediatric tertiary centre of Allergy and Immunology of São Paulo, Brazil, between 1986 and 2018 with a confirmed diagnosis of CHS. Data were obtained from medical records. Demographic aspects, family history, clinical findings, laboratory data, diagnosis, treatment and outcome were described. A total of 14 patients (five male) were included. Clinical manifestations were first recognized at a median age of two months (at birth-20 months). Median age at diagnosis was 1.7 years (0–5 years). All patients had recurrent infections. Albinism was present in 13 patients and silvery or light hair was present in 14. Seven patients developed hemophagocytic lymphohistiocytosis (HLH); the median age at the diagnosis of HLH was 5.7 years (2.6–6.7 years) and the median interval between the diagnosis of CHS and HLH was 3.3 years (0–5 years). Four of the most recently diagnosed patients underwent bone marrow transplantation (BMT). Nine patients are deceased, and one was lost to follow-up. The median age of death was 6.7 years (3.8–22 years). Five patients died of HLH, one of lymphoma, and three of infection. All the patients who had HLH before the year of 2000 died of HLH. The two most recently diagnosed patients with HLH were able to cure the HLH, although they died of other causes. Four patients are alive, three of them after successful BMT. Thirty years of follow up showed an improvement in the prognosis in patients with CHS. The better understanding of the underlying biological mechanisms of HLH allowed the standardization of management protocols, resulting in survival improvement. BMT is the only treatment that can change CHS prognosis, which emphasizes the need for early identification of the disease.
2013-11-06 | Modeling neural crest induction, melanocyte specification, and disease-related pigmentation defects in hESCs and patient-specific iPSCs.
Melanocytes are pigment-producing cells of neural crest (NC) origin that are responsible for protecting the skin against UV irradiation. Pluripotent stem cell (PSC) technology offers a promising approach for studying human melanocyte development and disease. Here, we report that timed exposure to activators of WNT, BMP, and EDN3 signaling triggers the sequential induction of NC and melanocyte precursor fates under dual-SMAD-inhibition conditions. Using a SOX10::GFP human embryonic stem cell (hESC) reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human NC induction. Subsequent maturation of hESC-derived melanocytes yields pure populations that match the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak syndrome and Chediak-Higashi syndrome patient-specific induced PSCs (iPSCs) faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during NC induction and enable the generation of pure populations of human iPSC-derived melanocytes for faithful modeling of pigmentation disorders.
other
2025-10-01 | S1535 Systematic Review of Hermansky-Pudlak Syndrome-Associated Colitis: Clinical Presentation, Diagnostic Features, Treatment Responses, and Outcomes
Introduction: Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction, and granulomatous colitis that clinically resembles inflammatory bowel disease (IBD). Due to significant diagnostic overlap, accurate identification of HPS-associated colitis is frequently delayed, affecting patient outcomes. Methods: A systematic review was performed in accordance with PRISMA guidelines. A comprehensive search of PubMed and Google Scholar identified 928 records. After removing 595 duplicates, 333 articles were screened, with 93 full texts reviewed. Ultimately, 29 case reports or series describing 46 unique patients with confirmed HPS-associated colitis were included. Patient demographics, clinical presentations, diagnostic delays, therapeutic strategies, and clinical outcomes were systematically evaluated. Results: Patients presented at a median age of 47 years, predominantly women (54%), with significant representation from Puerto Rican ancestry (46%). Common presenting symptoms included diarrhea (80%), hematochezia (78%), abdominal pain (70%), and fever (17%). Notably, diagnostic delays were extensive, commonly due to initial misdiagnoses as Crohn’s disease or infectious colitis. Therapeutically, biologics (used in 61% of cases) demonstrated superior efficacy compared to steroids (63%), immunomodulators (59%), and 5-ASA (43%). ICU admissions occurred in 9%, primarily due to severe hemorrhagic complications, and overall mortality was high at 13%, mostly related to multisystem organ failure post-surgery. Conclusion: HPS-associated colitis presents considerable diagnostic challenges, with frequent misdiagnoses and treatment complexities. Biologics emerge as the most effective therapeutic option. Increased awareness and early differentiation from classic IBD are essential to reduce diagnostic delays and improve outcomes.
2025-07-05 | Non-melanoma skin cancer and HPV in persons with albinism: a call for research investment.
Persons with albinism (PWA) have excessively high risks of non-melanoma skin cancer (NMSC) if not protected from ultraviolet (UV) radiation exposures, a situation which occurs too often amongst affected persons in sub-Saharan Africa. Certain countries in Eastern and Southern Africa, where levels of UV radiation are high, also have amongst the world's highest national-level prevalence of oculocutaneous albinism. Cutaneous HPV infections, particularly β-HPVs, may be co-factors with UV in skin carcinogenesis. If this is the case, there may be a pivotal potential for NMSC risk reduction via suitable vaccine development in all at-risk populations, and with the greatest individual-level benefit in PWA. With this background, and amidst climate change-induced increases in UV exposures, the research funding and scientific community are urged to prioritise HPV research on skin carcinogenesis in PWA. In the current perspective, we summarise: (1) the putative co-role of HPV with UV in skin carcinogenesis; (2) the possible implications of a potential HPV role in NMSC carcinogenesis; (3) the risks of skin cancer in PWA in the African setting; and (4) the research needs on HPV and NMSC in PWA, including the sensitivities and ethical responsibilities of undertaking such research amongst the PWA community in the African context.
2025-02-04 | Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7
Commander is an endosome associated sixteen protein assembly that associates with the sorting nexin 17 (SNX17) cargo adaptor to regulate cell surface recycling of internalised integral membrane proteins including integrins and lipoprotein receptors. Mutations in Commander are causative for Ritscher-Schinzel syndrome (RSS), a multiorgan developmental disease associated with a core triad of cerebellar-cardiac-craniofacial malformation. Here, using unbiased proteomics and computational modelling, we identify leucine rich melanocyte differentiation associated (LRMDA) as a novel Commander binding protein. Using recombinant protein reconstitution, we show that LRMDA simultaneously associates with Commander and active RAB32, and, by revealing that LRMDA and SNX17 share a common mechanism of Commander association, establish the mutually exclusive nature of RAB32-LRMDA-Commander and SNX17-Commander assemblies. From functional analysis in human melanocytes, we establish an essential role for RAB32-LRMDA-Commander in melanosome biogenesis and pigmentation and reveal a distinct functional role for SNX17-Commander in this organelle biogenesis pathway. We reveal how LRMDA mutations, causative for oculocutaneous albinism type 7 (OCA7), a hypopigmentation disorder accompanied by poor visual acuity, uncouple RAB32 and Commander binding thereby establishing the mechanistic basis of this disease. Our discovery and characterisation of this alternative Commander assembly establishes an unrecognised plasticity of Commander function within a highly complex organelle biogenesis pathway. This extends Commander function beyond the confines of SNX17-mediated cell surface recycling into RAB32-family mediated biogenesis of lysosome-related organelles and, potentially, other RAB32 regulated pathways including host-pathogen defence mechanisms. Our work also extends the breath of Commander pathway dysfunction for human disease.
2021-02-22 | Management of aggressive posterior retinopathy of prematurity in oculocutaneous albinism.
A male infant, born preterm at 32 weeks of gestation, was referred at 36-week postmenstrual age for retinopathy of prematurity (ROP) screening. He had nystagmus, generalised hypopigmentation of skin, hair and eyes with preaxial polydactyly. The fundus was depigmented with prominently visible choroidal vessels. The retinal vessels were dilated, tortuous at zone 1. There was presence of arcading, shunting of vessels with presence of vitreous haemorrhage in the left eye. A diagnosis of aggressive posterior retinopathy of prematurity (APROP) in association with oculocutaneous albinism (OCA) was made.Half-dose intravitreal bevacizumab was used to treat the vascular condition. After 2 weeks, there was complete regression of APROP with a completely mature retina observed at 4 months post-treatment. Herein, we describe the role of red-free light for screening ROP in infants with OCA; challenges in the management of ROP with laser photocoagulation compared with intravitreal anti-vascular endothelial growth factor therapy.
2019-02-28 | Crohn’s-like acute severe colitis associated with Hermansky-Pudlak syndrome: A case report
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet storage pool deficiency and systemic complications associated with ceroid deposition in the reticuloendothelial system. HPS types 1 and 4 are associated with Crohn's disease (CD)-like gastrointestinal disorders, such as granulomatous enterocolitis or perianal disease. Cases of colitis can be particularly severe and, before the use of anti-tumor necrosis factor alpha (TNFα) therapy had become common, were reported as showing poor responsiveness to medical treatment.We present the case of a 51-year-old albino woman who presented with acute severe colitis that led to the diagnosis of HPS. Histologic findings of biopsy samples showed chronic inflammation with deep ulcerations, and granulomas without caseous necrosis. Molecular genetic analysis confirmed HPS type 1, with a homozygous 27 base-pair deletion in exon 20 of the HPS1 gene. Once the patient's bleeding diathesis was corrected by platelet transfusion, the granulomatous colitis responded dramatically to a medical treatment regimen that included corticosteroids, azathioprine and infliximab; this regimen is similar to that used in CD treatment. Although it remains unclear if the granulomatous enterocolitis in HPS is due to ceroid deposition or reflects the co-existence of CD and HPS, the fact that this case of HPS-related granulomatous colitis responded to the same therapeutic approach used in CD suggests that this type of colitis may result from HPS patients' genetic susceptibility to CD.We report a case of severe colitis that led to the diagnosis of HPS, which was responsive to azathioprine and infliximab.
small molecules
2026-06-18 | Ampyrone is a direct agonist of human tyrosinase and a potential therapeutic for hypopigmentation disorders.
Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a human TYR construct, we developed high-throughput screening methods, in cell confirmatory assays employing 13C-tyrosine tracing, and computational analysis techniques, and identified ampyrone (4-aminoantipyrine) as a TYR activator. Ampyrone increased the in vitro catalytic activity of the human recombinant intra-melanosomal domain of TYR (hTYR) and its hypomorphic variant, Pro406Leu (P406L), a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, mouse OCA2 melanocytes, as well as 3-dimensional (3D) human skin cultures. Computational studies provided additional insight into the effects of direct TYR agonists on enzyme activity. Our results identified ampyrone as a lead candidate for TYR activation, potentially supporting the development of therapies for patients with genetic and acquired diseases of hypopigmentation.
2026-06-05 | Targeting melanosome pH is an effective method for the treatment of oculocutaneous albinism.
Oculocutaneous albinism (OCA) is a genetic condition associated with impaired visual acuity and increased skin cancer risk. When OCA is due to defects in melanosome ion transport, abnormally acidic conditions in the melanosome lumen inhibit tyrosinase, the critical pigment synthetic enzyme. Hence, a therapeutic approach that optimizes melanosome pH to increase pigment production presents a potential treatment for OCA and a method for decreasing skin cancer risk. Here, we report that reduction in sAC ( ADCY10 ) activity via naturally occurring human variants in ADCY10 restores OCA pigmentation, and sAC inhibition increases melanin synthesis in both human and mouse OCA models. These findings demonstrate that targeting melanosome pH is an effective, previously untapped therapeutic strategy for OCA and elevated skin cancer risk.
2026-02-07 | A Case Report on Oculocutaneous Albinism
Aims: Understanding the epidemiology, pathophysiology, clinical manifestations, causative mutations and management of oculocutaneous albinism by reporting a case of a 17 year old affected by this disease. Study Design: Case report: 17-year-old male presenting oculocutaneous albinism who presented for an ophthalmology consultation due to a profound decrease in visual acuity, associated with nystagmus and photophobia that had been progressing since early childhood. Discussion and Literature Review: We will comprehensively examine all aspects of oculocutaneous albinism by reviewing the literature on its epidemiology, pathophysiology, clinical manifestations, differential diagnosis, treatment, and prognosis. Conclusion: Advances in molecular diagnostics have significantly enhanced the detection of causative mutations, enabling improved clinical management and genetic counseling. Emerging therapeutic approaches, including pharmacological interventions, offer promising avenues for correcting pigmentation defects.
2025-12-25 | OCA2 deficiency enhances TPC2 channel activity to reduce melanosomal pH and pigment production.
Albinism is a heterogeneous inherited disorder with at least 21 known causative genes. Clinically, interpreting the potential digenic or oligogenic effects of the variants is a big challenge. We identified digenic mutations in a Chinese individual with oculocutaneous albinism, carrying a loss-of-function mutation in the Cl- (chloride) channel gene OCA2 (c.808-3C>G) and an unreported gain-of-function mutation in the Na+/Ca2+ channel gene TPCN2 (p.Ala24Val), which was confirmed by patch-clamp analysis. We further demonstrated that Cl- bilaterally modulated TPC2 activity by patch clamping: cytosolic high Cl- inhibited but luminal high Cl- enhanced TPC2 channel activity. Using CRISPR/Cas9-mediated knockout cell models and knockin mouse models, we confirmed that OCA2 modulated TPC2 activity by influencing melanosomal pH and pigment production. Mice mimicking double heterozygotes for the OCA2 loss-of-function p.Val443Ile and the TPCN2 gain-of-function p.Arg210Cys exhibited synergistic hypopigmentation in both fur and retina, phenocopying the albinism patient with digenic loss-of-function OCA2 and gain-of-function TPCN2 heterozygous mutations. This study provides experimental evidence supporting an oligogenic mode of inheritance in albinism, pinpoints melanosomal ion homeostasis as a key pathogenic mechanism and potential therapeutic target, and establishes a generalized research framework for elucidating gene-gene interactions in heterogeneous inherited disorders, especially for the channelopathies.
2025-12-10 | A Case Report on Oculocutaneous albinism
Aims: Understanding the epidemiology, pathophysiology, clinical manifestations, causative mutations and management of oculocutaneous albinism by reporting a case of a 7-year-old child affected by this disease Study Design: Case report. Case Report: 7-year-old child presenting oculocutaneous albinism who presented for an ophthalmology consultation due to a profound decrease in visual acuity, associated with nystagmus and photophobia that had been progressing since early childhood Discussion and Literature Review: We will comprehensively examine all aspects of oculocutaneous albinism by reviewing the literature on its epidemiology, pathophysiology, clinical manifestations, differential diagnosis, treatment, and prognosis. Conclusion: Advances in molecular diagnostics have significantly enhanced the detection of causative mutations, enabling improved clinical management and genetic counseling. Emerging therapeutic approaches, including pharmacological interventions, offer promising avenues for correcting pigmentation defects.
proteins
2026-09-24 | A novel TYR variant implicated in oculocutaneous albinism type 1 (OCA1): a study in an indigenous population in Southern Brazil.
Oculocutaneous albinism (OCA) is a genetic condition with an estimated global prevalence of 1 in 17,000, though this varies across populations. The Kaingang are a Brazilian Indigenous group belonging to the Macro-Jê language family. Report a novel variant TYR:c.704A>G; p.Tyr235Cys in homozygosity among individuals of Kaingang ethnicity in the state of Rio Grande do Sul, Brazil. A commercial next-generation sequencing (NGS-based) panel for hypopigmentation and oculocutaneous albinism was applied to one saliva sample; exome sequencing (ES) was performed using NGS in another individual; and the remaining 14 individuals were genotyped by quantitative real-time (qPCR). The detection of this variant in 14 individuals from the same Indigenous Territory, within an estimated population of 6,000, yields an allele frequency of 0.05, suggesting a founder effect in this population. The affected individuals were not closely related, suggesting that the recurrence of the variant is not due to recent consanguinity but rather to population structure and inheritance from a common ancestor. In addition, NGS and ES have proven essential for accurate diagnosis of oculocutaneous albinism and for molecular reclassification of cases previously diagnosed clinically. This study contributes to understanding the molecular profile of albinism in Brazilian Indigenous populations, sheds light on historically underrepresented communities in genetic research and has the potential to inform targeted interventions and public health policies for individuals with albinism in these communities.
2026-07-17 | The Role of SLC24A5 (NCKX5) in Human Skin Pigmentation: The Importance of Cation Transport Activity.
Human pigmentation is determined by melanosome development and melanin production through melanogenesis, a process regulated by melanogenic proteins. A single nucleotide polymorphism (A111T) in the SLC24A5 gene, which encodes the K⁺-dependent Na⁺/Ca2⁺ exchanger NCKX5, is a major determinant of normal variation in human skin and iris color. Despite the suggested role of NCKX5 in skin pigmentation, its ion transport function in melanogenesis remains unclear. To address this, we silenced SLC24A5 in pigmented human MNT1 melanoma cells using CRISPR/Cas9-mediated knockout. Loss of NCKX5 resulted in a marked reduction in eumelanin levels and the formation of abnormal, non-uniform melanosomes with defective fibrillar structure. To evaluate the functional role of NCKX5, we reconstituted depigmented cells with myc-tagged NCKX5 variants, including the transport-deficient mutant D383N. Reconstitution with the A111 variant of NCKX5 restored eumelanin synthesis more effectively than the T111 variant, whereas the D383N variant failed to rescue pigmentation. Moreover, the addition of the lysosomotropic weak base NH4Cl to the growth medium, which neutralizes the acidic pH of intracellular organelles, markedly increased eumelanin content in depigmented cells lacking NCKX5, suggesting a link between NCKX5-mediated Ca2+ transport activity in the TGN and melanosomal pH regulation. We also discuss the many NCKX5 mutants that have been reported to affect pigmentation in both humans (Oculocutaneous albinism or OCA6) and animals in the context of their potential effects on NCKX5-mediated Ca2+ transport activity.
2026-02-18 | A Dosage-Dependent Dominant-Negative Mechanism of SLC45A2(W74R) in Autosomal Dominant Oculocutaneous Albinism Revealed by Zebrafish Modeling.
To investigate the clinical characteristics of autosomal dominant oculocutaneous albinism (OCA) and functionally validate the heterozygous SLC45A2(W74R) variant using a zebrafish model. Three members of a Korean family with OCA underwent comprehensive clinical examinations. Targeted panel and genome sequencing were performed on the proband, and Sanger sequencing was performed on all affected family members. To assess the pathogenicity of the genetic variant, a slc45a2 knockout (KO) zebrafish model was generated using CRISPR technology. All three affected patients exhibited hair and iris hypopigmentation, with variable foveal hypoplasia and nystagmus. A heterozygous c.220T>C:p.(W74R) variant in SLC45A2 was identified and was absent in gnomAD v4.1. Multiple in silico predictions supported its pathogenicity (AlphaMissense: 0.993, CADD: 29.6, REVEL: 0.951). Genome sequencing revealed no additional pathogenic or common hypomorphic variants in other known OCA-related genes. The slc45a2 KO zebrafish exhibited a typical albino phenotype, which was rescued by melanocyte-specific expression of normal SLC45A2 but not by the SLC45A2(W74R) variant. Furthermore, the SLC45A2(W74R) variant suppressed pigmentation in heterozygous KO, but not in wild-type zebrafish, indicating a dominant-negative effect in a dosage-dependent manner. This study demonstrated that a heterozygous c.220T>C:p.(W74R) variant in SLC45A2 causes variable expressivity of OCA in a dominant inherited manner, and this variant interferes with melanogenesis in zebrafish. This study expands the mode of inheritance in OCA and provides crucial functional validation that is important for genetic counseling.
2026-01-20 | Co-option of Lysosomal Machinery for Biomineralization
Summary Biomineralization first emerged ∼600 million years ago, giving rise to novel strategies for buoyancy, locomotion, and defense. 1 Sponges are the only metazoans that build a silica-based skeleton, 2 and the cellular and molecular mechanisms underlying their silicification process are much less understood than in diatoms and land plants, the other two major biosilicifiers. Here, we show that the cells specialized for sponge biosilicification, termed sclerocytes, highly express lysosomal-associated genes, including the V-H + -ATPase (VHA) proton pump, oculocutaneous albinism type 2 (OCA2) anion channels, cathepsin-L proteins, silicateins, TMEM55A, TMEM192, TMEM199, and multiple other proteins involved with lysosomal maintenance and degradation. Further, we demonstrate that VHA protein localizes to the sclerocyte silica deposition vesicle (SDV) and that VHA-dependent SDV acidification is essential for silica spicule formation. This function mirrors the localization and role of VHA in diatom biosilicification, 3 while in land plants, acidification occurs extracellularly in the xylem and is driven by a different proton pump, the plasma membrane P-type H + -ATPase. 4,5 These results indicate that vesicle acidification is a shared mechanism for silica handling in sponges, diatoms, and plants. We also found that genes homologous to the plant silicon efflux transporter Lsi2, 6 which belong to the same gene family as OCA2, 7,8 are upregulated in sclerocytes. Using Hybridization Chain Reaction Fluorescence In Situ Hybridization (HCR-FISH), we found that sponge Lsi2 genes are expressed in sclerocytes, corroborating prior phylogenetic and transcriptomic evidence that Lsi2 homologs are involved in sponge and diatom silicic acid transport. 7–10 Taking into account previous work showing that VHA, cathepsins, and other lysosomal-associated genes have been associated with calcification across a remarkable range of eukaryotes including coccolitophores, 11 foraminifera, 12 sea urchins, 13 bryozoans, 14 crustaceans, 15 mollusks, 16 and mammals, 17 we posit that the various biomineralization mechanisms observed throughout the tree of life arose convergently through the co-option of an ancestral lysosomal gene toolkit.
2026-01-12 | First Report of Oculocutaneous Albinism Type I Among Baka Pygmies From Cameroon.
Oculocutaneous albinism type 1 (OCA1) caused by pathogenic variants of the TYR gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in skin, hair, and eyes. We had the opportunity to examine five East Cameroon Baka rainforest hunter-gatherers (historically called "Pygmies") with albinism and belonging to three different families. Screening of known albinism genes revealed a homozygous missense variant in the TYR gene, NM_000372.5: c.1109T>C; p.Met370Thr. In addition, one patient was also hemizygous for a variant in GPR143, the gene involved in ocular albinism (OA1). Another patient was also heterozygous for the common African and Afro-American 2.7-kb deletion in the OCA2 gene indicating admixture of one parent with neighboring Nzimé Bantu-speaking farmers. This is the first report of the occurrence of OCA1 in African rainforest hunter-gatherers.
gene therapies
2026-07-29 | Ocular Safety and Efficacy of AAV-mediated Tyrosinase Gene Augmentation in a Nonhuman Primate Model.
Oculocutaneous albinism type 1 (OCA1) is an inherited disorder caused by tyrosinase ( TYR ) gene mutations. Affected individuals experience visual impairment and severe photosensitivity from ocular hypomelanosis, with no current treatments. We evaluated the safety and efficacy of a TYR -encoding adeno-associated virus (AAV) vector in healthy rhesus macaques as a potential OCA1 treatment. A novel AAV2-based capsid (ATX002) was packaged with the human VMD2 promoter and TYR (h TYR ) fused with mGreenLantern (mGL). Two adult rhesus macaques were injected with ATX002-hVMD2-h TYR - mGL subretinally (OD) and intravitreally (OS). Safety and efficacy were assessed via comprehensive ophthalmic examination, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinography at baseline and defined timepoints up to 12 weeks post-injection, followed by post-mortem immunohistochemistry (IHC). Both subretinal doses induced localized hypermelanosis by 3 weeks post-injection, which persisted through the study endpoint and was accompanied by measurable thickening of the retinal pigment epithelium (RPE) on SD-OCT. Histological IHC confirmed successful RPE transduction via robust mGL fluorescence, corroborating in vivo findings by revealing localized RPE hyperplasia and transgene-expressing cells adjacent to regions of de novo hypermelanosis. Intravitreal delivery did not induce any changes to the RPE. Transient uveitis was observed but successfully managed with anti-inflammatory treatment. Subretinal AAV- TYR delivery is a safe and effective approach with the potential to induce RPE pigmentation. These findings support the use of AAV- TYR gene therapy for OCA1, demonstrating efficacy and a manageable safety profile in a large-animal model, and provide a critical bridge toward human clinical translation.
2026-07-04 | Combining modeling approaches for rapid preclinical evaluation of retinal gene therapy
The pathway to developing genetic treatments for rare, monogenic ocular disorders has historically been impeded by limited options in preclinical testing pipelines. In this issue of Molecular Therapy Advances, Dr. Aman George and colleagues navigate this challenge by presenting a proof-of-principle investigation of an adeno-associated virus (AAV)-based gene therapy strategy for oculocutaneous albinism type 1A (OCA1A).1 Building on prior work2 using a constitutive promoter, their approach delivers a human TYROSINASE (TYR) transgene under the stringent transcriptional control of a human BESTROPHIN (VMD2) promoter to restore melanin synthesis.
2026-07-02 | Systemic, RPE-directed AAV- Tyrosinase therapy restores ocular pigmentation in an OCA1 mouse model
Abstract Oculocutaneous albinism type 1 (OCA1) is a pigmentation disorder caused by biallelic tyrosinase ( TYR ) mutations, an essential enzyme for melanin synthesis. TYR inactivity results in loss of hair, skin, and eye pigment, which is detrimental for ocular function. Hypopigmentation of iris, retinal pigment epithelium (RPE), and choroid results in severe photosensitivity and low visual acuity. There are currently no FDA-approved pigment restoring therapies for OCA1, making therapeutic development an unmet clinical need. To address this gap, we have advanced an adeno-associated viral (AAV)-mediated Tyr replacement approach for OCA1 ocular pigment restoration. We evaluated the optimal viral delivery strategy and vector cell-type specificity for iris, RPE, and choroid pigmentation in an OCA1 mouse model, testing intraocular and systemic viral delivery methods in conjunction with viral constructs of varying RPE-specificity. Early, systemic delivery of an RPE-directed AAV- Tyr construct, AAV9.2yf-VMD2- Tyr , achieved widespread ocular pigment rescue with minimal off-target expression in non-ocular tissues. Animals treated with AAV9.2yf-VMD2- Tyr demonstrated reduced photophobic behavior compared to untreated controls, indicating that ocular pigmentation restores a debilitating functional consequence of OCA1. Our findings establish a foundation for clinical translation of an AAV- TYR therapy aimed at improving light sensitivity, glare, and low vision through pigment restoration in patients with OCA1.
2026-05-15 | Gene therapy induces pigmentation in induced pluripotent stem cell-derived retinal pigment epithelium of OCA1A patients and albino rat eye.
Oculocutaneous albinism type 1A (OCA1A), the most severe and prevalent form of albinism, is caused by recessive mutations in the TYROSINASE gene. We provide proof-of-principle of an effective gene therapy-based strategy for future human application in OCA1A patients. Here, we show that an AAV-based TYROSINASE gene delivery under the control of human BESTROPHIN promoter VMD2 can successfully induce pigmentation in human retinal pigment epithelium (RPE) monolayer tissue, derived from OCA1A patients, via induced pluripotent stem cells. Pigmentation was induced without significantly compromising the RPE monolayer tissue integrity, apical-basal polarization, cellular morphology, or functionally relevant gene expression patterns. This human RPE-specific construct was able to induce pigmentation in albino rat RPE and choroid when delivered into eyes via suprachoroidal injection. Our strategy can be potentially employed to not only induce pigmentation but also efficiently deliver other target genes, without significantly compromising monolayer tissue integrity and viability of human RPE, a prime gene therapy target tissue for many degenerative disorders affecting vision.
2026-03-11 | Oculocutaneous albinism variants in 28 consanguineous families and functional classification of a pathogenic deep intron variant in TYR.
Oculocutaneous albinism (OCA) are genetically and clinically heterogeneous recessive disorders with at least 23 associated genes. Isolated OCA is characterized by hypopigmentation in the skin, hair, and eyes combined with ocular abnormalities. Hermansky Pudlak syndrome (HPS) and Chediak-Higaski syndrome are syndromic forms of OCA, distinguished by immunological and hematological symptoms in addition to hypopigmentation and ocular anomalies. Targeted clinical care is crucial for the patients and molecular genetic diagnosis is important for classification of patients. Current diagnostic yield is approximately 70%, and a high proportion of patients are heterozygous for pathogenic variants in OCA genes, suggesting the presence of disease-causing non-coding variants. We describe here next generation sequencing (NGS) analysis, including copy number variant (CNV) analysis, of 28 consanguineous families, comprising a total of 136 individuals presenting with OCA. We provide a molecular genetic diagnosis in all 28 families. Noteworthy, five families (18%) had pathogenic variants in a gene associated with HPS, showing the importance of an in-depth molecular genetic investigation, which should be offered to persons with albinism. Furthermore, we report the first deep intron variant in TYR causing OCA and show by minigene analysis that the variant causes inclusion of a pseudoexon.
cell therapies
2025-05-19 | Hermansky-Pudlak Syndrome: From Molecular Pathogenesis to Targeted Therapies.
Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder caused by defects in lysosome-related organelles (LROs) in various tissues, including platelets, melanocytes, and endothelial cells. Key features of HPS include oculocutaneous albinism, bleeding tendency, and, in some cases, pulmonary fibrosis, granulomatous colitis, and immunodeficiency. The condition is linked to mutations in 11 genes involved in the formation of LROs. Currently, treatment options for HPS are limited and often ineffective. Though cell and gene therapies have been explored for melanosomes and epithelial cells, there is limited knowledge about their application to platelets and endothelial cells. Understanding the detailed mechanisms of HPS pathogenesis is crucial, and using induced pluripotent stem cell (iPSC) models may provide valuable insights into the disease's molecular processes, aiding the development of new treatments. In this review, we will focus on the genetics and molecular mechanisms of HPS, on its clinical manifestations and current therapeutic approaches, highlighting the need for further research into the disease mechanisms and potential innovative therapies.
2025-05-01 | Two in One: Bilateral Orthotopic Lung Transplant and Mitral Valve Replacement in a Case of Hermansky-Pudlak Syndrome
Abstract Intro: Hermanksy-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction, and, in severe forms, organ dysfunction manifest as colitis or pulmonary fibrosis (PF). Global prevalence estimates between 1-2 per million, but within select populations, such as Puerto Rico, prevalence is 1 in 1,800, constituting half of existing HPS cases. HPS subtypes 1, 2, and 4 have the highest incidence of PF due to lysosomal dysfunction and proliferative inflammatory response similar to IPF. Among Puerto Ricans with HPS, subtype 1 predominates, which has the highest incidence of PF. HPS pulmonary fibrosis (HPS-PF) has a gradual onset; however, our patient had a rapid progression to respiratory failure complicated by pulmonary hypertension (PH) and mitral regurgitation (MR) requiring complex medical and surgical management. Case: A pleasant 49-year-old Puerto Rican male with HPS presented with acute, progressive dyspnea in August. He was subsequently admitted to the ICU for acute hypoxic respiratory failure requiring BiPAP and was started on high dose steroids. With minimal improvement and persistent baseline 12-15L of O2 support, he was transferred to UNMC for transplant evaluation. CT chest revealed significant UIP/NSIP pattern of PF. Evaluation demonstrated moderate-severe MR and group 3 PH. Despite prolonged diuresis, treprostinil, and steroids, his oxygen requirements persisted. Multidisciplinary transplant evaluation was performed, and he was subsequently listed for lung transplant. In October, he deteriorated requiring continuous BiPAP until he succumbed to hypoxic bradycardia resulting in cardiac arrest with subsequent return of spontaneous circulation and cannulation for VV ECMO as bridge to lung transplant. Bilateral orthotopic lung transplant (BOLT) and simultaneous mitral valve repair occurred the following day. Postoperative course was complicated by prolonged ventilator wean necessitating tracheostomy; otherwise, the patient recovered as anticipated. Discussion: This case demonstrates the complex, multidisciplinary management required for HPS-PF. The patient's acute respiratory failure did not resolve with steroids leading to investigations of cardiac causes. Transthoracic echocardiogram revealed MR and elevated pulmonary artery systolic pressure. Further optimization of respiratory function included diuresis to euvolemia followed by right heart catheterization which demonstrated precapillary PH in the setting of PF. Treatment ensued with inhaled prostacyclin therapy in combination with diuretics. The question became the severity of mitral regurgitation and what its impact may be on lung transplant. Transesophageal echocardiogram performed perioperatively demonstrated severe MR necessitating complex valve replacement prior to BOLT. A novel feat allowing for successful lung transplant in HPS-PF.
2022-03-21 | In vitro disease modeling of oculocutaneous albinism type 1 and 2 using human induced pluripotent stem cell-derived retinal pigment epithelium.
Oculocutaneous albinism (OCA) encompasses a set of autosomal recessive genetic conditions that affect pigmentation in the eye, skin, and hair. OCA patients display reduced best-corrected visual acuity, reduced to absent ocular pigmentation, abnormalities in fovea development, and/or abnormal decussation of optic nerve fibers. It has been hypothesized that improving eye pigmentation could prevent or rescue some of the vision defects. The goal of the present study was to develop an in vitro model for studying pigmentation defects in human retinal pigment epithelium (RPE). We developed a "disease in a dish" model for OCA1A and OCA2 types using induced pluripotent stem cells to generate RPE. The RPE is a monolayer of cells that are pigmented, polarized, and polygonal in shape, located between the neural retina and choroid, with an important role in vision. Here we show that RPE tissue derived in vitro from OCA patients recapitulates the pigmentation defects seen in albinism, while retaining the apical-basal polarity and normal polygonal morphology of the constituent RPE cells.
2019-08-30 | Chediak–Higashi syndrome: Lessons from a single-centre case series
Chediak–Higashi syndrome (CHS) is a rare and potentially fatal autosomal recessive disease characterized by frequent bacterial infections, bleeding tendency, oculocutaneous albinism, photosensitivity and progressive neurologic dysfunction. Owing to the rarity of this condition, the objective of this study was to describe patients with CHS. Retrospective evaluation of patients followed in a paediatric tertiary centre of Allergy and Immunology of São Paulo, Brazil, between 1986 and 2018 with a confirmed diagnosis of CHS. Data were obtained from medical records. Demographic aspects, family history, clinical findings, laboratory data, diagnosis, treatment and outcome were described. A total of 14 patients (five male) were included. Clinical manifestations were first recognized at a median age of two months (at birth-20 months). Median age at diagnosis was 1.7 years (0–5 years). All patients had recurrent infections. Albinism was present in 13 patients and silvery or light hair was present in 14. Seven patients developed hemophagocytic lymphohistiocytosis (HLH); the median age at the diagnosis of HLH was 5.7 years (2.6–6.7 years) and the median interval between the diagnosis of CHS and HLH was 3.3 years (0–5 years). Four of the most recently diagnosed patients underwent bone marrow transplantation (BMT). Nine patients are deceased, and one was lost to follow-up. The median age of death was 6.7 years (3.8–22 years). Five patients died of HLH, one of lymphoma, and three of infection. All the patients who had HLH before the year of 2000 died of HLH. The two most recently diagnosed patients with HLH were able to cure the HLH, although they died of other causes. Four patients are alive, three of them after successful BMT. Thirty years of follow up showed an improvement in the prognosis in patients with CHS. The better understanding of the underlying biological mechanisms of HLH allowed the standardization of management protocols, resulting in survival improvement. BMT is the only treatment that can change CHS prognosis, which emphasizes the need for early identification of the disease.
2013-11-06 | Modeling neural crest induction, melanocyte specification, and disease-related pigmentation defects in hESCs and patient-specific iPSCs.
Melanocytes are pigment-producing cells of neural crest (NC) origin that are responsible for protecting the skin against UV irradiation. Pluripotent stem cell (PSC) technology offers a promising approach for studying human melanocyte development and disease. Here, we report that timed exposure to activators of WNT, BMP, and EDN3 signaling triggers the sequential induction of NC and melanocyte precursor fates under dual-SMAD-inhibition conditions. Using a SOX10::GFP human embryonic stem cell (hESC) reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human NC induction. Subsequent maturation of hESC-derived melanocytes yields pure populations that match the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak syndrome and Chediak-Higashi syndrome patient-specific induced PSCs (iPSCs) faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during NC induction and enable the generation of pure populations of human iPSC-derived melanocytes for faithful modeling of pigmentation disorders.
other
2025-10-01 | S1535 Systematic Review of Hermansky-Pudlak Syndrome-Associated Colitis: Clinical Presentation, Diagnostic Features, Treatment Responses, and Outcomes
Introduction: Hermansky-Pudlak Syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction, and granulomatous colitis that clinically resembles inflammatory bowel disease (IBD). Due to significant diagnostic overlap, accurate identification of HPS-associated colitis is frequently delayed, affecting patient outcomes. Methods: A systematic review was performed in accordance with PRISMA guidelines. A comprehensive search of PubMed and Google Scholar identified 928 records. After removing 595 duplicates, 333 articles were screened, with 93 full texts reviewed. Ultimately, 29 case reports or series describing 46 unique patients with confirmed HPS-associated colitis were included. Patient demographics, clinical presentations, diagnostic delays, therapeutic strategies, and clinical outcomes were systematically evaluated. Results: Patients presented at a median age of 47 years, predominantly women (54%), with significant representation from Puerto Rican ancestry (46%). Common presenting symptoms included diarrhea (80%), hematochezia (78%), abdominal pain (70%), and fever (17%). Notably, diagnostic delays were extensive, commonly due to initial misdiagnoses as Crohn’s disease or infectious colitis. Therapeutically, biologics (used in 61% of cases) demonstrated superior efficacy compared to steroids (63%), immunomodulators (59%), and 5-ASA (43%). ICU admissions occurred in 9%, primarily due to severe hemorrhagic complications, and overall mortality was high at 13%, mostly related to multisystem organ failure post-surgery. Conclusion: HPS-associated colitis presents considerable diagnostic challenges, with frequent misdiagnoses and treatment complexities. Biologics emerge as the most effective therapeutic option. Increased awareness and early differentiation from classic IBD are essential to reduce diagnostic delays and improve outcomes.
2025-07-05 | Non-melanoma skin cancer and HPV in persons with albinism: a call for research investment.
Persons with albinism (PWA) have excessively high risks of non-melanoma skin cancer (NMSC) if not protected from ultraviolet (UV) radiation exposures, a situation which occurs too often amongst affected persons in sub-Saharan Africa. Certain countries in Eastern and Southern Africa, where levels of UV radiation are high, also have amongst the world's highest national-level prevalence of oculocutaneous albinism. Cutaneous HPV infections, particularly β-HPVs, may be co-factors with UV in skin carcinogenesis. If this is the case, there may be a pivotal potential for NMSC risk reduction via suitable vaccine development in all at-risk populations, and with the greatest individual-level benefit in PWA. With this background, and amidst climate change-induced increases in UV exposures, the research funding and scientific community are urged to prioritise HPV research on skin carcinogenesis in PWA. In the current perspective, we summarise: (1) the putative co-role of HPV with UV in skin carcinogenesis; (2) the possible implications of a potential HPV role in NMSC carcinogenesis; (3) the risks of skin cancer in PWA in the African setting; and (4) the research needs on HPV and NMSC in PWA, including the sensitivities and ethical responsibilities of undertaking such research amongst the PWA community in the African context.
2025-02-04 | Identification of a RAB32-LRMDA-Commander membrane trafficking complex reveals the molecular mechanism of human oculocutaneous albinism type 7
Commander is an endosome associated sixteen protein assembly that associates with the sorting nexin 17 (SNX17) cargo adaptor to regulate cell surface recycling of internalised integral membrane proteins including integrins and lipoprotein receptors. Mutations in Commander are causative for Ritscher-Schinzel syndrome (RSS), a multiorgan developmental disease associated with a core triad of cerebellar-cardiac-craniofacial malformation. Here, using unbiased proteomics and computational modelling, we identify leucine rich melanocyte differentiation associated (LRMDA) as a novel Commander binding protein. Using recombinant protein reconstitution, we show that LRMDA simultaneously associates with Commander and active RAB32, and, by revealing that LRMDA and SNX17 share a common mechanism of Commander association, establish the mutually exclusive nature of RAB32-LRMDA-Commander and SNX17-Commander assemblies. From functional analysis in human melanocytes, we establish an essential role for RAB32-LRMDA-Commander in melanosome biogenesis and pigmentation and reveal a distinct functional role for SNX17-Commander in this organelle biogenesis pathway. We reveal how LRMDA mutations, causative for oculocutaneous albinism type 7 (OCA7), a hypopigmentation disorder accompanied by poor visual acuity, uncouple RAB32 and Commander binding thereby establishing the mechanistic basis of this disease. Our discovery and characterisation of this alternative Commander assembly establishes an unrecognised plasticity of Commander function within a highly complex organelle biogenesis pathway. This extends Commander function beyond the confines of SNX17-mediated cell surface recycling into RAB32-family mediated biogenesis of lysosome-related organelles and, potentially, other RAB32 regulated pathways including host-pathogen defence mechanisms. Our work also extends the breath of Commander pathway dysfunction for human disease.
2021-02-22 | Management of aggressive posterior retinopathy of prematurity in oculocutaneous albinism.
A male infant, born preterm at 32 weeks of gestation, was referred at 36-week postmenstrual age for retinopathy of prematurity (ROP) screening. He had nystagmus, generalised hypopigmentation of skin, hair and eyes with preaxial polydactyly. The fundus was depigmented with prominently visible choroidal vessels. The retinal vessels were dilated, tortuous at zone 1. There was presence of arcading, shunting of vessels with presence of vitreous haemorrhage in the left eye. A diagnosis of aggressive posterior retinopathy of prematurity (APROP) in association with oculocutaneous albinism (OCA) was made.Half-dose intravitreal bevacizumab was used to treat the vascular condition. After 2 weeks, there was complete regression of APROP with a completely mature retina observed at 4 months post-treatment. Herein, we describe the role of red-free light for screening ROP in infants with OCA; challenges in the management of ROP with laser photocoagulation compared with intravitreal anti-vascular endothelial growth factor therapy.
2019-02-28 | Crohn’s-like acute severe colitis associated with Hermansky-Pudlak syndrome: A case report
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, platelet storage pool deficiency and systemic complications associated with ceroid deposition in the reticuloendothelial system. HPS types 1 and 4 are associated with Crohn's disease (CD)-like gastrointestinal disorders, such as granulomatous enterocolitis or perianal disease. Cases of colitis can be particularly severe and, before the use of anti-tumor necrosis factor alpha (TNFα) therapy had become common, were reported as showing poor responsiveness to medical treatment.We present the case of a 51-year-old albino woman who presented with acute severe colitis that led to the diagnosis of HPS. Histologic findings of biopsy samples showed chronic inflammation with deep ulcerations, and granulomas without caseous necrosis. Molecular genetic analysis confirmed HPS type 1, with a homozygous 27 base-pair deletion in exon 20 of the HPS1 gene. Once the patient's bleeding diathesis was corrected by platelet transfusion, the granulomatous colitis responded dramatically to a medical treatment regimen that included corticosteroids, azathioprine and infliximab; this regimen is similar to that used in CD treatment. Although it remains unclear if the granulomatous enterocolitis in HPS is due to ceroid deposition or reflects the co-existence of CD and HPS, the fact that this case of HPS-related granulomatous colitis responded to the same therapeutic approach used in CD suggests that this type of colitis may result from HPS patients' genetic susceptibility to CD.We report a case of severe colitis that led to the diagnosis of HPS, which was responsive to azathioprine and infliximab.
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