RARE DISEASE
X-linked intellectual disability, Nascimento type
X-linked intellectual disability, Nascimento type
X-linked intellectual disability, Nascimento type
Synonyms: X-linked intellectual disability-nail dystrophy-seizures syndrome
Synonyms: X-linked intellectual disability-nail dystrophy-seizures syndrome
Synonyms: X-linked intellectual disability-nail dystrophy-seizures syndrome
Drug discovery
55
papers
On emerging therapies
Overview
X-linked intellectual disability, Nascimento type is a rare X-linked recessive disorder caused by UBE2A gene mutations, characterized by severe intellectual disability, profound speech impairment, dysmorphic features (synophrys, prominent supraorbital ridges, macrostomia), generalized hirsutism, onychodystrophy, and seizures [1][3][6]. Additional findings include myxedematous skin changes, micropenis, and structural CNS abnormalities [3][6][16]. Diagnosis relies on clinical evaluation, neuroimaging, and molecular confirmation of UBE2A variants [6][16]. Management focuses on multidisciplinary supportive care [1][6].
Burden
High care dependency due to severe intellectual disability and lifelong communication limitations [1][6]
Associated comorbidities: 50% risk of seizures, surgical needs (e.g., congenital cataracts, tetralogy of Fallot) [3][6]
Psychosocial/financial strain on families, compounded by diagnostic delays averaging >5 years [6][16]
Therapies
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
55 drug discovery papers about X-linked intellectual disability, Nascimento type. Recent publications:
55 drug discovery papers about X-linked intellectual disability, Nascimento type. Recent publications:
categories:
Small molecules
small molecules
2026-03-06 | PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
Arts syndrome is a rare X-linked recessive neurodevelopmental disorder arising from pathogenic variants in PRPS1, which encodes phosphoribosyl pyrophosphate synthetase 1-an enzyme essential for de novo nucleotide biosynthesis. Affected individuals typically exhibit sensorineural hearing loss, intellectual disability, cerebellar ataxia, and recurrent infections. However, despite the severity of these clinical manifestations, therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder. In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies. Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved. Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes. Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology. Collectively, these findings delineate key cellular mechanisms underlying PRPS1-associated neurodevelopmental pathology and identify NAD＋ metabolic augmentation as a promising therapeutic avenue for Arts syndrome and related PRPS1-mediated disorders.
2026-02-26 | Emerging role of KDM5C in X-linked intellectual disability based on human genetic data and zebrafish models.
Claes-Jensen syndrome is a rare X-linked syndromic neurodevelopmental disorder by pathogenic variants in lysine specific demethylase 5C (KDM5C), a lysine-specific histone demethylase. In this study, clinical evaluations were conducted in affected individuals and carrier females. X-chromosome inactivation (XCI) assays were performed to assess genotype-phenotype correlations. Functional studies evaluated variant effects on RNA transcription, protein expression, and stability. Zebrafish models were used for in vivo validation. RNA sequencing with KEGG and GO analyses identified dysregulated genes and pathways, further confirmed in zebrafish. Two novel KDM5C variants NM_004187.5:c.3019del and NM_004187.5:c.782-2A>T were identified in unrelated families with X-linked ID. Affected males presented with short stature, microcephaly, language delay, and intellectual disability, while carrier females showed milder features including learning difficulties and short stature. Skewed XCI in some carriers suggested a role in phenotypic variability. Both variants impair RNA transcription, protein expression and stability. Zebrafish models recapitulated neurodevelopmental and behavioral abnormalities. Transcriptomic analyses revealed disrupted antiviral and interferon-related signaling, implicating aberrant immune activation. Pharmacologic inhibition of the Toll-like receptor pathway ameliorated mutant phenotypes, highlighting neuroinflammation as a potential therapeutic target for KDM5C-related disorders. These findings expand the mutational spectrum of KDM5C-associated ID and uncover a novel pathogenic mechanism between KDM5C dysfunction, protein instability, and dysregulated inflammatory signaling.
2026-01-21 | A Zebrafish Seizure Model of cblX Syndrome Reveals a Dose-Dependent Response to mTor Inhibition.
Mutations in the transcriptional co-factor HCFC1 cause methylmalonic aciduria and homocystinemia, cblX type (cblX) (MIM#309541), non-syndromic X-linked intellectual disability (XLID), and focal epilepsy. Zebrafish studies have revealed increased activation of the Akt/mTor signaling pathway after mutation of hcfc1a, one ortholog of HCFC1. mTOR hyperactivation is linked to seizures, and its inhibition alleviates epilepsy in other preclinical models. We hypothesized that mTor overactivity in hcfc1a mutant zebrafish increases seizure susceptibility and/or severity. We employed a two-concentration model of the seizure-inducing agent, pentylenetetrazol (PTZ), with or without pretreatment of the mTor inhibitor, torin1. Mutation of hcfc1a did not alter the response to PTZ at sub-optimal concentrations, and the pharmaceutical inhibition of mTor using the compound Torin1 reduced response to 1 µM PTZ, but only in a dose-dependent manner. Higher doses of mTor inhibition did not reduce the seizure response in mutant larvae but were effective in wildtype siblings. These data suggest that inhibition of mTor in an hcfc1a-deficient background leads to a reaction that differs from the traditional response observed in wildtype siblings. Collectively, we present a model that can be used to test dose-response and the development of combinatorial treatment approaches in a high-throughput manner.
2025-11-01 | Spermine synthase in Snyder-Robinson syndrome and cancer.
Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.
2025-09-20 | The Christianson syndrome protein, sodium hydrogen exchanger isoform 6, is required for fat accumulation.
Mutations in NHE6 (human gene name SLC9A6) lead to the rare X-linked disorder Christianson syndrome (CS) characterized by intellectual disability, autism and ataxia. NHE6 is a Na+/H+ exchanger that regulates pH and ionic equilibria across endosomal membranes in a variety of tissues, although its non-neuronal role is understudied. A common co-morbidity in CS is low body weight, with body mass index in the 3-5th percentile range. In the present study, we use a Nhe6KO mouse model of CS to demonstrate a role for NHE6 in fat accumulation and glucose homeostasis. On both chow and a high-fat diet, Nhe6KO mice displayed lower body weight and decreased fat accumulation in adipose tissue. By contrast, glycogen accumulation was strongly increased in liver of Nhe6KO mice on a high-fat diet. Knockdown of NHE6 (NHE6 KD) in 3T3L1 adipocytes resulted in smaller lipid droplets, pointing to a cell autonomous role in fat accumulation. NHE6 KD adipocytes also exhibit dysregulation of insulin-responsive uptake of fatty acids, glucose and Fe/transferrin, as well as the cell surface translocation of the corresponding transporters. Furthermore, we observed selective downregulation of key components of the insulin signalling pathway that could be restored using the Na+/H+ exchanger mimetic monensin or the V-ATPase inhibitor bafilomycin, pointing to pH dysregulation as the underlying defect. These findings establish NHE6 as a novel contributor to energy metabolism with implications for CS patients. KEY POINTS: NHE6 is an endosomal Na+/H+ exchanger mutated in Christianson syndrome. Nhe6 null mice accumulate less fat and weigh less than control animals. In adipocytes, NHE6 knockdown reduces insulin-stimulated fatty acid and glucose uptake. NHE6 exerts proteostatic control over multiple components of the insulin signalling pathway.
proteins
2025-11-15 | Astrocytic Chromatin Remodeler ATRX Gates Hippocampal Memory Consolidation Through Metabolic and Synaptic Regulation.
Astrocytes are increasingly recognized as active regulators of synaptic transmission and memory, yet the epigenetic mechanisms underlying their contribution to cognitive processes remain poorly defined. Here, we investigated the role of the chromatin remodeler ATRX in astrocytes by generating mice with inducible, astrocyte-specific Atrx deletion (aiKO) using tamoxifen administration at postnatal days 10-12, resulting in ATRX loss in approximately half of hippocampal and cortical astrocytes. Transcriptomic profiling of hippocampal tissue at 1 and 3 months revealed differentially expressed genes, with early enrichment for cytoskeletal and immune pathways and later dysregulation of energy metabolism, ion transport, and synaptic gene sets. Electrophysiological recordings from CA1 pyramidal neurons in aiKO slices demonstrated increased neuronal excitability and decreased frequency of spontaneous excitatory postsynaptic currents, indicating non-cell-autonomous neuronal dysfunction. Morphological analysis identified a transient reduction in dendritic branching at 1 month and a selective loss of thin dendritic spines by 3 months, without changes in total dendrite length or overall spine density. Behaviorally, aiKO mice displayed normal locomotion, anxiety, and short-term memory, but exhibited deficits in 24-h novel object recognition and long-term spatial memory in the Morris water maze. These findings demonstrate that ATRX-mediated chromatin remodeling in astrocytes is essential for maintaining hippocampal transcriptional homeostasis, neuronal function, and long-term memory. Our results highlight a critical role for astrocytic epigenetic regulation in cognitive processes and suggest that astrocyte dysfunction may contribute to the pathogenesis of ATR-X syndrome and related intellectual disability disorders, underscoring the importance of targeting multiple cell types for therapeutic intervention.
2024-03-02 | PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.
2014-10-06 | Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality.
The phosphatidylinositol glycan class A (PIGA) protein is a member of the glycosylphosphatidylinositol anchor pathway. Germline mutations in PIGA located at Xp22.2 are thought to be lethal in males. However, a nonsense mutation in the last coding exon was recently described in two brothers with multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) who survived through birth likely because of the hypomorphic nature of the truncated protein, but died in their first weeks of life. Here, we report on a frameshift mutation early in the PIGA cDNA (c.76dupT; p.Y26Lfs*3) that cosegregates with the disease in a large family diagnosed with a severe syndromic form of X-linked intellectual disability. Unexpectedly, CD59 surface expression suggested the production of a shorter PIGA protein with residual functionality. We provide evidence that the second methionine at position 37 may be used for the translation of a 36 amino acids shorter PIGA. Complementation assays confirmed that this shorter PIGA cDNA was able to partially rescue the surface expression of CD59 in a PIGA-null cell line. Taken together, our data strongly suggest that the early frameshift mutation in PIGA produces a truncated hypomorph, which is sufficient to rescue the lethality in males but not the MCAHS2-like phenotype.
oligonucleotides
2022-03-02 | Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities.
Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.
gene therapies
2026-08-09 | Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan-Herndon-Dudley Syndrome Mouse Model.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
2026-06-16 | X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review.
To report the clinical manifestations and genetic diagnosis of a female patient with X-linked intellectual developmental disorder-93 (XLID93, OMIM#300659) caused by a BRWD3 gene mutation. Systematically summarize the clinical and genetic characteristics of reported female cases and analyze the genotype-phenotype correlation. A case of XLID93 in a 1-year-and-3-month-old girl was reported. Perform whole-exome sequencing, qPCR copy number verification, X-chromosome inactivation analysis, and three-dimensional protein structure prediction for the child in this case; systematically search relevant databases, and summarize and analyze the phenotypes and genotypes of 5 female patients with BRWD3 mutations reported in the literature to date. The patient was a 1-year-and-3-month-old female presenting with delayed gross motor development, unable to stand or walk independently; poor fine motor skills; high muscle tone in the upper limbs and low muscle tone in the lower limbs. Her head circumference was 48.2 cm (95th-97th). She had slightly wide eye spacing, a low nasal bridge, a prominent forehead, a short neck, and a low posterior hairline. There was a heterozygous deletion variation of exon (loss1, EXON 21-30) in the BRWD3 gene of the patient. First-generation verification showed that both parents of the proband were wild-type; this mutation is a de novo mutation, and it is currently impossible to determine whether it is located on the paternal or maternal X chromosome. Protein structure prediction shows that this deletion results in the complete loss of a bromodomain, which may significantly affect the protein function. Through X-chromosome inactivation testing, the inactivation ratio of the maternally derived X-chromosome of the proband was about 89%, indicating non-random inactivation. In summary, the analysis of the clinical and genetic characteristics of five female patients with XLID93 syndrome caused by BRWD3 gene mutations shows that their core clinical phenotypes have obvious commonalities, mainly manifested as: developmental delay (60%), neurological manifestations (60%), head circumference greater than the 95th percentile (60%), and special facial features (40%), with the overall clinical manifestations being milder than those in the male population. Notably, all three female patients who underwent X chromosome inactivation (XCI) testing exhibited skewed XCI, and the severity of the clinical phenotype was closely related to the direction and degree of XCI skewing: patients with preferential inactivation of the mutant X chromosome had milder clinical manifestations (patient 1 had mild cognitive impairment in early childhood); in contrast, patients with preferential inactivation of the normal X chromosome and active expression of the mutant X chromosome had more severe phenotypes (patient 4 had macrocephaly, special facial features, and developmental delay). This further clarifies the important significance of XCI testing in the genotype-phenotype correlation analysis of female patients with MRX93 syndrome. Clinicians should recommend early genetic testing for children with intellectual disability, language development delay, macrocephaly, or epilepsy. For female patients, X-chromosome inactivation testing should also be completed. Early diagnosis can improve long-term outcomes and prevent the birth of severely affected male children in the same family.
2026-04-05 | Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome.
Christianson syndrome is an x-linked recessive neurodevelopmental and neurodegenerative condition caused by mutations to the SLC9A6 gene encoding NHE6, a sodium-hydrogen exchanger critical for regulating endosomal pH. Using an adeno-associated viral (AAV) vector targeting Purkinje cells (PHP.eB-L7-Slc9a6-GFP), we recently performed functional complementation studies to demonstrate that mutation to the rat Slc9a6 gene causes a Christianson syndrome-relevant cerebellar phenotype in the shaker rat. We carried out a longitudinal study evaluating the impact of gene replacement targeting Purkinje cells on ataxia and tremor in the shaker rat. Further, in a smaller follow-up study, we tested administration of AAV9-CAG-hSLC9A6 to determine whether key molecular and motor findings could be replicated with a more clinically relevant viral construct. In both experimental cohorts, we performed molecular studies to evaluate expression of NHE6 and key cerebellar markers. Administration of either of PHP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in both the molecular and motor phenotypes. The abundance of each disease-relevant cerebellar proteins was strongly correlated to motor ataxia, but less so to tremor. Further, while ataxia and tremor were initially strongly correlated early in the disease progression, this relationship weakened over time. These findings impact future SLC9A6-targeted gene therapy efforts for Christianson syndrome and support gene replacement as a potentially viable therapeutic strategy. Common markers associated with cerebellar degeneration are much more strongly tied to ataxia than to tremor, indicating that ataxia may be more tied related to degenerative processes than tremor.
2025-12-11 | Concomitant Mosaic Turner Syndrome and Congenital Adrenal Hyperplasia in 1 of 3 Patients of USP9X Variant-Associated Autism Spectrum Disorder.
X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the USP9X gene. This study reports on 3 patients diagnosed with autism spectrum disorder (ASD), highlighting novel genetic findings. Among the 3 patients, two male siblings exhibited a novel USP9X gene missense variant, while the third, a female, presented a unique deletion of the USP9X gene alongside adrenal insufficiency and mosaic Turner syndrome. This variant has not been reported in public databases and may influence ASD development. This report documents the first instance of a triple diagnosis of XLID99, Turner syndrome, and congenital adrenal hyperplasia. Findings underline the significance of genetic evaluation in ASD for identifying rare and complex diagnoses.
2025-08-27 | Case Report: Identification of a novel hemizygous missense RPL10 gene variant in two unrelated patients.
The X-linked syndromic intellectual developmental disorder-35 (MRXS35; OMIM#300998) is caused by variants in the RPL10 gene (OMIM*312173) on chromosome Xq28. Patients with MRXS35 mainly present with intellectual disability (ID), psychomotor development delay, speech delay, short stature, craniofacial anomalies, hypotonia, seizures, gastrointestinal problems, genitourinary anomalies, cardiac anomalies, eye defects, and hearing loss. Herein, we are the first to report two unrelated Chinese patients with the same novel hemizygous missense RPL10 gene variant. Two male patients from two different families were admitted to the hospital for genetic counseling. In the first months of life, both newborns presented with congenital laryngeal stridor, feeding difficulties, neonatal pneumonia, neonatal hypoglycemia, dysmorphic features, and bilateral cryptorchidism. At his last clinical evaluation at 9 years of age, case II presented with ID, speech delay, short stature, and craniofacial anomalies. Whole-exome sequencing identified the same hemizygous missense RPL10 gene variant (NM_006013.5:c.347G>A, p.Arg116Gln) in each patient, inherited from their respective mothers. The functional analysis of this variant in vitro demonstrated that this missense RPL10 gene variant (c.347G>A) reduced the mRNA expression of the RPL10 gene, thereby decreasing synthesis of the RPL10 protein. Our in vitro functional analysis indicated a loss-of-function effect of RPL10 gene variants.
other
2026-04-13 | Phenotypic variability in female individuals with the NAA10 missense variants p.(L126R), p.(L126V), or p.(F128L) leading to NAA10-related syndrome.
BACKGROUND: NAA10-related syndrome is an exceptionally rare X-linked disorder caused by variants in the N-alpha-acetyltransferase 10 (NAA10) gene. Despite its role in acetylating nearly half of the human proteome, establishing genotype-phenotype correlations remains challenging due to the limited number of documented cases and the extremely broad phenotypic spectrum. METHODS: We performed exome sequencing and clinical phenotyping of three female patients. To investigate the pathogenic mechanisms without interference from endogenous protein, we generated the first viable NAA10 knockout (ΔNAA10) cell line using CRISPR/Cas9 in the 8-MG-BA glioblastoma line. This null-background model allowed for the analysis of GFP-tagged patient variants, specifically focusing on colocalization with the auxiliary subunit NAA15. RESULTS: Our study expands the global landscape of NAA10-related diseases—now totaling 145 individuals with 46 pathogenic variants—by describing three females with de novo NAA10 variants clustering closely within the N-acetyltransferase domain: p.(L126R), p.(L126V), and p.(F128L). The first patient exhibits severe global developmental delay, neuroimaging anomalies, and congenital cardiac defects and remains non-verbal. The second patient experiences developmental delays, particularly in motor skills and language. The third patient also presents with severe global developmental delay with significant motor impairments and remains non-verbal. Localization studies in the ΔNAA10 cells revealed that while the p.L126V variant maintained near-wild-type protein stability and colocalization with NAA15, the bulky p.L126R and disruptive p.F128L substitutions severely impaired NatA complex formation and altered cellular distribution. This study expands the known clinical landscape by detailing the phenotypic spectrum of three female patients, including two entirely novel cases described here for the first time. We aimed to explore how specific variants in the catalytic domain affect protein stability and NatA complex formation, helping to explain the diverse clinical manifestations observed in affected females. CONCLUSION: This study highlights the broad phenotypic spectrum of NAA10-related syndrome and demonstrates that clinical severity is driven by the specific amino acid substitution rather than the position alone. With 145 cases now identified globally, the need for precision modeling is critical. Our novel ΔNAA10 cell line proves to be a robust tool for linking specific biochemical defects to clinical phenotypes, potentially offering new insights into this complex syndrome.
small molecules
2026-03-06 | PRPS1 (p.V42L) Mutation in Arts Syndrome Induces Aberrant Neural Stem Cell Development and Neuronal Senescence-Like Phenotype: Rescue by Nicotinamide Mononucleotide Supplementation.
Arts syndrome is a rare X-linked recessive neurodevelopmental disorder arising from pathogenic variants in PRPS1, which encodes phosphoribosyl pyrophosphate synthetase 1-an enzyme essential for de novo nucleotide biosynthesis. Affected individuals typically exhibit sensorineural hearing loss, intellectual disability, cerebellar ataxia, and recurrent infections. However, despite the severity of these clinical manifestations, therapeutic interventions remain limited, largely due to an incomplete understanding of the cellular pathophysiology underlying the disorder. In this study, we generated patient-specific induced pluripotent stem cells harboring the PRPS1 p.V42L variant and differentiated them into neural stem cells (NSCs) and neurons to elucidate disease mechanisms and explore potential therapeutic strategies. Patient-derived NSCs demonstrated significantly reduced proliferative capacity, aberrant nuclear morphology, and increased neuronal senescence, while mitochondrial integrity and function were largely preserved. Neurons differentiated from these NSCs exhibited impaired neurite outgrowth and reduced branching complexity, indicative of disrupted neurodevelopmental processes. Notably, supplementation with nicotinamide mononucleotide, a precursor of nicotinamide adenine dinucleotide (NAD＋), partially ameliorated defects in NSC proliferation, nuclear architecture, and neuronal morphology. Collectively, these findings delineate key cellular mechanisms underlying PRPS1-associated neurodevelopmental pathology and identify NAD＋ metabolic augmentation as a promising therapeutic avenue for Arts syndrome and related PRPS1-mediated disorders.
2026-02-26 | Emerging role of KDM5C in X-linked intellectual disability based on human genetic data and zebrafish models.
Claes-Jensen syndrome is a rare X-linked syndromic neurodevelopmental disorder by pathogenic variants in lysine specific demethylase 5C (KDM5C), a lysine-specific histone demethylase. In this study, clinical evaluations were conducted in affected individuals and carrier females. X-chromosome inactivation (XCI) assays were performed to assess genotype-phenotype correlations. Functional studies evaluated variant effects on RNA transcription, protein expression, and stability. Zebrafish models were used for in vivo validation. RNA sequencing with KEGG and GO analyses identified dysregulated genes and pathways, further confirmed in zebrafish. Two novel KDM5C variants NM_004187.5:c.3019del and NM_004187.5:c.782-2A>T were identified in unrelated families with X-linked ID. Affected males presented with short stature, microcephaly, language delay, and intellectual disability, while carrier females showed milder features including learning difficulties and short stature. Skewed XCI in some carriers suggested a role in phenotypic variability. Both variants impair RNA transcription, protein expression and stability. Zebrafish models recapitulated neurodevelopmental and behavioral abnormalities. Transcriptomic analyses revealed disrupted antiviral and interferon-related signaling, implicating aberrant immune activation. Pharmacologic inhibition of the Toll-like receptor pathway ameliorated mutant phenotypes, highlighting neuroinflammation as a potential therapeutic target for KDM5C-related disorders. These findings expand the mutational spectrum of KDM5C-associated ID and uncover a novel pathogenic mechanism between KDM5C dysfunction, protein instability, and dysregulated inflammatory signaling.
2026-01-21 | A Zebrafish Seizure Model of cblX Syndrome Reveals a Dose-Dependent Response to mTor Inhibition.
Mutations in the transcriptional co-factor HCFC1 cause methylmalonic aciduria and homocystinemia, cblX type (cblX) (MIM#309541), non-syndromic X-linked intellectual disability (XLID), and focal epilepsy. Zebrafish studies have revealed increased activation of the Akt/mTor signaling pathway after mutation of hcfc1a, one ortholog of HCFC1. mTOR hyperactivation is linked to seizures, and its inhibition alleviates epilepsy in other preclinical models. We hypothesized that mTor overactivity in hcfc1a mutant zebrafish increases seizure susceptibility and/or severity. We employed a two-concentration model of the seizure-inducing agent, pentylenetetrazol (PTZ), with or without pretreatment of the mTor inhibitor, torin1. Mutation of hcfc1a did not alter the response to PTZ at sub-optimal concentrations, and the pharmaceutical inhibition of mTor using the compound Torin1 reduced response to 1 µM PTZ, but only in a dose-dependent manner. Higher doses of mTor inhibition did not reduce the seizure response in mutant larvae but were effective in wildtype siblings. These data suggest that inhibition of mTor in an hcfc1a-deficient background leads to a reaction that differs from the traditional response observed in wildtype siblings. Collectively, we present a model that can be used to test dose-response and the development of combinatorial treatment approaches in a high-throughput manner.
2025-11-01 | Spermine synthase in Snyder-Robinson syndrome and cancer.
Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.
2025-09-20 | The Christianson syndrome protein, sodium hydrogen exchanger isoform 6, is required for fat accumulation.
Mutations in NHE6 (human gene name SLC9A6) lead to the rare X-linked disorder Christianson syndrome (CS) characterized by intellectual disability, autism and ataxia. NHE6 is a Na+/H+ exchanger that regulates pH and ionic equilibria across endosomal membranes in a variety of tissues, although its non-neuronal role is understudied. A common co-morbidity in CS is low body weight, with body mass index in the 3-5th percentile range. In the present study, we use a Nhe6KO mouse model of CS to demonstrate a role for NHE6 in fat accumulation and glucose homeostasis. On both chow and a high-fat diet, Nhe6KO mice displayed lower body weight and decreased fat accumulation in adipose tissue. By contrast, glycogen accumulation was strongly increased in liver of Nhe6KO mice on a high-fat diet. Knockdown of NHE6 (NHE6 KD) in 3T3L1 adipocytes resulted in smaller lipid droplets, pointing to a cell autonomous role in fat accumulation. NHE6 KD adipocytes also exhibit dysregulation of insulin-responsive uptake of fatty acids, glucose and Fe/transferrin, as well as the cell surface translocation of the corresponding transporters. Furthermore, we observed selective downregulation of key components of the insulin signalling pathway that could be restored using the Na+/H+ exchanger mimetic monensin or the V-ATPase inhibitor bafilomycin, pointing to pH dysregulation as the underlying defect. These findings establish NHE6 as a novel contributor to energy metabolism with implications for CS patients. KEY POINTS: NHE6 is an endosomal Na+/H+ exchanger mutated in Christianson syndrome. Nhe6 null mice accumulate less fat and weigh less than control animals. In adipocytes, NHE6 knockdown reduces insulin-stimulated fatty acid and glucose uptake. NHE6 exerts proteostatic control over multiple components of the insulin signalling pathway.
proteins
2025-11-15 | Astrocytic Chromatin Remodeler ATRX Gates Hippocampal Memory Consolidation Through Metabolic and Synaptic Regulation.
Astrocytes are increasingly recognized as active regulators of synaptic transmission and memory, yet the epigenetic mechanisms underlying their contribution to cognitive processes remain poorly defined. Here, we investigated the role of the chromatin remodeler ATRX in astrocytes by generating mice with inducible, astrocyte-specific Atrx deletion (aiKO) using tamoxifen administration at postnatal days 10-12, resulting in ATRX loss in approximately half of hippocampal and cortical astrocytes. Transcriptomic profiling of hippocampal tissue at 1 and 3 months revealed differentially expressed genes, with early enrichment for cytoskeletal and immune pathways and later dysregulation of energy metabolism, ion transport, and synaptic gene sets. Electrophysiological recordings from CA1 pyramidal neurons in aiKO slices demonstrated increased neuronal excitability and decreased frequency of spontaneous excitatory postsynaptic currents, indicating non-cell-autonomous neuronal dysfunction. Morphological analysis identified a transient reduction in dendritic branching at 1 month and a selective loss of thin dendritic spines by 3 months, without changes in total dendrite length or overall spine density. Behaviorally, aiKO mice displayed normal locomotion, anxiety, and short-term memory, but exhibited deficits in 24-h novel object recognition and long-term spatial memory in the Morris water maze. These findings demonstrate that ATRX-mediated chromatin remodeling in astrocytes is essential for maintaining hippocampal transcriptional homeostasis, neuronal function, and long-term memory. Our results highlight a critical role for astrocytic epigenetic regulation in cognitive processes and suggest that astrocyte dysfunction may contribute to the pathogenesis of ATR-X syndrome and related intellectual disability disorders, underscoring the importance of targeting multiple cell types for therapeutic intervention.
2024-03-02 | PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.
The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.
2014-10-06 | Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality.
The phosphatidylinositol glycan class A (PIGA) protein is a member of the glycosylphosphatidylinositol anchor pathway. Germline mutations in PIGA located at Xp22.2 are thought to be lethal in males. However, a nonsense mutation in the last coding exon was recently described in two brothers with multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) who survived through birth likely because of the hypomorphic nature of the truncated protein, but died in their first weeks of life. Here, we report on a frameshift mutation early in the PIGA cDNA (c.76dupT; p.Y26Lfs*3) that cosegregates with the disease in a large family diagnosed with a severe syndromic form of X-linked intellectual disability. Unexpectedly, CD59 surface expression suggested the production of a shorter PIGA protein with residual functionality. We provide evidence that the second methionine at position 37 may be used for the translation of a 36 amino acids shorter PIGA. Complementation assays confirmed that this shorter PIGA cDNA was able to partially rescue the surface expression of CD59 in a PIGA-null cell line. Taken together, our data strongly suggest that the early frameshift mutation in PIGA produces a truncated hypomorph, which is sufficient to rescue the lethality in males but not the MCAHS2-like phenotype.
oligonucleotides
2022-03-02 | Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities.
Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.
gene therapies
2026-08-09 | Central Thyroid Hormone Deprivation Disrupts Cortical Cilia and Oligodendrocyte Lineage in an Allan-Herndon-Dudley Syndrome Mouse Model.
Allan-Herndon-Dudley syndrome (AHDS) is an X-linked neurodevelopmental disorder caused by loss of the thyroid hormone (TH) transporter MCT8, resulting in central TH deprivation and disrupted cortical maturation, cognition, and motor control. MCT8/OATP1C1 double-knockout (dKO) mice faithfully model the human disease, recapitulating its postnatal hypomyelination, neuromotor impairment, and cortical defects. Yet, cell-type-specific pathologies underlying AHDS remain insufficiently defined. To uncover cellular perturbations by TH deprivation, we performed single-nucleus RNA sequencing on cortex and attached cerebral nuclei from P21 WT and dKO mice. Differential gene expression, trajectory, pseudotime and gene-set enrichment analyses, and NeuronChat-based cell-cell communication modeling were integrated with LC-MS/MS-based TH quantification, immunofluorescence, and RNAscope. In 48 clusters identified across cortical and striatal regions, we found increased numbers of GABAergic striatal D1 and D2 neurons in dKO mice, whereas mature oligodendrocytes were reduced. Trajectory analysis uncovered a bifurcation within the oligodendrocyte lineage, separating WT and dKO maturation paths and producing a dKO branch with gene profiles reminiscent of a stress-responsive, demyelination-prone state, despite largely preserved expression of core myelination genes. Trajectory analyses revealed shifted pseudotime states and distinct gene expression profiles in glutamatergic intratelencephalic and corticothalamic lineages of dKO mice. Differential gene expression patterns showed limited correspondence to Slc16a2 or Slco1c1 transcript levels but aligned strongly with published TH deprivation datasets, validating our findings and indicating that cellular perturbations are largely established by P21. Cell-cell communication analysis revealed a network imbalance favoring GABAergic over glutamatergic signaling, accompanied by altered neurexin-neuroligin interactions. In parallel, we identified a coordinated dysregulation of cilia-related genes, together with changes in cilia length and number. Our findings provide the first single-cell-level cortical map of AHDS brain pathology, revealing cilia defects, excitation-inhibition imbalance, differing pseudotime trajectories in glutamatergic neuronal populations and altered oligodendrocyte maturation, with actionable candidate genes such as Lama2, Litaf, and Dcc, as promising targets for future mechanistic and therapeutic exploration in AHDS. Slc16a2 and Slco1c1 transcript abundance alone did not predict cellular vulnerability, highlighting TH availability rather than transporter expression as key determinant of cell-type sensitivity and core mechanism for cortical network homeostasis.
2026-06-16 | X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review.
To report the clinical manifestations and genetic diagnosis of a female patient with X-linked intellectual developmental disorder-93 (XLID93, OMIM#300659) caused by a BRWD3 gene mutation. Systematically summarize the clinical and genetic characteristics of reported female cases and analyze the genotype-phenotype correlation. A case of XLID93 in a 1-year-and-3-month-old girl was reported. Perform whole-exome sequencing, qPCR copy number verification, X-chromosome inactivation analysis, and three-dimensional protein structure prediction for the child in this case; systematically search relevant databases, and summarize and analyze the phenotypes and genotypes of 5 female patients with BRWD3 mutations reported in the literature to date. The patient was a 1-year-and-3-month-old female presenting with delayed gross motor development, unable to stand or walk independently; poor fine motor skills; high muscle tone in the upper limbs and low muscle tone in the lower limbs. Her head circumference was 48.2 cm (95th-97th). She had slightly wide eye spacing, a low nasal bridge, a prominent forehead, a short neck, and a low posterior hairline. There was a heterozygous deletion variation of exon (loss1, EXON 21-30) in the BRWD3 gene of the patient. First-generation verification showed that both parents of the proband were wild-type; this mutation is a de novo mutation, and it is currently impossible to determine whether it is located on the paternal or maternal X chromosome. Protein structure prediction shows that this deletion results in the complete loss of a bromodomain, which may significantly affect the protein function. Through X-chromosome inactivation testing, the inactivation ratio of the maternally derived X-chromosome of the proband was about 89%, indicating non-random inactivation. In summary, the analysis of the clinical and genetic characteristics of five female patients with XLID93 syndrome caused by BRWD3 gene mutations shows that their core clinical phenotypes have obvious commonalities, mainly manifested as: developmental delay (60%), neurological manifestations (60%), head circumference greater than the 95th percentile (60%), and special facial features (40%), with the overall clinical manifestations being milder than those in the male population. Notably, all three female patients who underwent X chromosome inactivation (XCI) testing exhibited skewed XCI, and the severity of the clinical phenotype was closely related to the direction and degree of XCI skewing: patients with preferential inactivation of the mutant X chromosome had milder clinical manifestations (patient 1 had mild cognitive impairment in early childhood); in contrast, patients with preferential inactivation of the normal X chromosome and active expression of the mutant X chromosome had more severe phenotypes (patient 4 had macrocephaly, special facial features, and developmental delay). This further clarifies the important significance of XCI testing in the genotype-phenotype correlation analysis of female patients with MRX93 syndrome. Clinicians should recommend early genetic testing for children with intellectual disability, language development delay, macrocephaly, or epilepsy. For female patients, X-chromosome inactivation testing should also be completed. Early diagnosis can improve long-term outcomes and prevent the birth of severely affected male children in the same family.
2026-04-05 | Viral vector-mediated SLC9A6 gene replacement reduces cerebellar motor and molecular abnormalities in the shaker rat model of Christianson syndrome.
Christianson syndrome is an x-linked recessive neurodevelopmental and neurodegenerative condition caused by mutations to the SLC9A6 gene encoding NHE6, a sodium-hydrogen exchanger critical for regulating endosomal pH. Using an adeno-associated viral (AAV) vector targeting Purkinje cells (PHP.eB-L7-Slc9a6-GFP), we recently performed functional complementation studies to demonstrate that mutation to the rat Slc9a6 gene causes a Christianson syndrome-relevant cerebellar phenotype in the shaker rat. We carried out a longitudinal study evaluating the impact of gene replacement targeting Purkinje cells on ataxia and tremor in the shaker rat. Further, in a smaller follow-up study, we tested administration of AAV9-CAG-hSLC9A6 to determine whether key molecular and motor findings could be replicated with a more clinically relevant viral construct. In both experimental cohorts, we performed molecular studies to evaluate expression of NHE6 and key cerebellar markers. Administration of either of PHP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in both the molecular and motor phenotypes. The abundance of each disease-relevant cerebellar proteins was strongly correlated to motor ataxia, but less so to tremor. Further, while ataxia and tremor were initially strongly correlated early in the disease progression, this relationship weakened over time. These findings impact future SLC9A6-targeted gene therapy efforts for Christianson syndrome and support gene replacement as a potentially viable therapeutic strategy. Common markers associated with cerebellar degeneration are much more strongly tied to ataxia than to tremor, indicating that ataxia may be more tied related to degenerative processes than tremor.
2025-12-11 | Concomitant Mosaic Turner Syndrome and Congenital Adrenal Hyperplasia in 1 of 3 Patients of USP9X Variant-Associated Autism Spectrum Disorder.
X-linked intellectual developmental disorder 99 (XLID99) is a rare neurodevelopmental disorder associated with mutations in the USP9X gene. This study reports on 3 patients diagnosed with autism spectrum disorder (ASD), highlighting novel genetic findings. Among the 3 patients, two male siblings exhibited a novel USP9X gene missense variant, while the third, a female, presented a unique deletion of the USP9X gene alongside adrenal insufficiency and mosaic Turner syndrome. This variant has not been reported in public databases and may influence ASD development. This report documents the first instance of a triple diagnosis of XLID99, Turner syndrome, and congenital adrenal hyperplasia. Findings underline the significance of genetic evaluation in ASD for identifying rare and complex diagnoses.
2025-08-27 | Case Report: Identification of a novel hemizygous missense RPL10 gene variant in two unrelated patients.
The X-linked syndromic intellectual developmental disorder-35 (MRXS35; OMIM#300998) is caused by variants in the RPL10 gene (OMIM*312173) on chromosome Xq28. Patients with MRXS35 mainly present with intellectual disability (ID), psychomotor development delay, speech delay, short stature, craniofacial anomalies, hypotonia, seizures, gastrointestinal problems, genitourinary anomalies, cardiac anomalies, eye defects, and hearing loss. Herein, we are the first to report two unrelated Chinese patients with the same novel hemizygous missense RPL10 gene variant. Two male patients from two different families were admitted to the hospital for genetic counseling. In the first months of life, both newborns presented with congenital laryngeal stridor, feeding difficulties, neonatal pneumonia, neonatal hypoglycemia, dysmorphic features, and bilateral cryptorchidism. At his last clinical evaluation at 9 years of age, case II presented with ID, speech delay, short stature, and craniofacial anomalies. Whole-exome sequencing identified the same hemizygous missense RPL10 gene variant (NM_006013.5:c.347G>A, p.Arg116Gln) in each patient, inherited from their respective mothers. The functional analysis of this variant in vitro demonstrated that this missense RPL10 gene variant (c.347G>A) reduced the mRNA expression of the RPL10 gene, thereby decreasing synthesis of the RPL10 protein. Our in vitro functional analysis indicated a loss-of-function effect of RPL10 gene variants.
other
2026-04-13 | Phenotypic variability in female individuals with the NAA10 missense variants p.(L126R), p.(L126V), or p.(F128L) leading to NAA10-related syndrome.
BACKGROUND: NAA10-related syndrome is an exceptionally rare X-linked disorder caused by variants in the N-alpha-acetyltransferase 10 (NAA10) gene. Despite its role in acetylating nearly half of the human proteome, establishing genotype-phenotype correlations remains challenging due to the limited number of documented cases and the extremely broad phenotypic spectrum. METHODS: We performed exome sequencing and clinical phenotyping of three female patients. To investigate the pathogenic mechanisms without interference from endogenous protein, we generated the first viable NAA10 knockout (ΔNAA10) cell line using CRISPR/Cas9 in the 8-MG-BA glioblastoma line. This null-background model allowed for the analysis of GFP-tagged patient variants, specifically focusing on colocalization with the auxiliary subunit NAA15. RESULTS: Our study expands the global landscape of NAA10-related diseases—now totaling 145 individuals with 46 pathogenic variants—by describing three females with de novo NAA10 variants clustering closely within the N-acetyltransferase domain: p.(L126R), p.(L126V), and p.(F128L). The first patient exhibits severe global developmental delay, neuroimaging anomalies, and congenital cardiac defects and remains non-verbal. The second patient experiences developmental delays, particularly in motor skills and language. The third patient also presents with severe global developmental delay with significant motor impairments and remains non-verbal. Localization studies in the ΔNAA10 cells revealed that while the p.L126V variant maintained near-wild-type protein stability and colocalization with NAA15, the bulky p.L126R and disruptive p.F128L substitutions severely impaired NatA complex formation and altered cellular distribution. This study expands the known clinical landscape by detailing the phenotypic spectrum of three female patients, including two entirely novel cases described here for the first time. We aimed to explore how specific variants in the catalytic domain affect protein stability and NatA complex formation, helping to explain the diverse clinical manifestations observed in affected females. CONCLUSION: This study highlights the broad phenotypic spectrum of NAA10-related syndrome and demonstrates that clinical severity is driven by the specific amino acid substitution rather than the position alone. With 145 cases now identified globally, the need for precision modeling is critical. Our novel ΔNAA10 cell line proves to be a robust tool for linking specific biochemical defects to clinical phenotypes, potentially offering new insights into this complex syndrome.
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