Pathogenic variants in TMEM184B cause a neurodevelopmental syndrome associated with alteration of metabolic signaling
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ABSTRACT:
PROVIDER: PRJNA1221920 | ENA |
REPOSITORIES: ENA
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Project description:Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric cases who have de novo heterozygous variants in TMEM184B. All individuals harbor rare missense or mRNA splicing changes and have neurodevelopmental deficits including developmental delay, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain, wherein many human disease-associated variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural development in vivo, we suppressed the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural neurons, aligning with symptoms of affected individuals. Ectopic TMEM184B expression resulted in dominant effects for Lys184Glu and Gly162Arg. However, in vivo complementation studies demonstrate that all other variants tested result in diminished protein function and indicate a haploinsufficiency basis for disease. Human induced pluripotent stem cells (iPSC) with monoallelic expression of Lys184Glu show mRNA disruptions in key metabolic pathways and molecules including those controlling mechanistic target of rapamycin (mTOR) activity. Expression of Lys184Glu and other variants increased apoptosis in cell lines and altered nuclear localization of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, further supporting disruptions to nutrient signaling pathways. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption likely through divergent molecular effects that all result in abnormal neural development.
2025-07-30 | GSE289220 | GEO
Project description: Not available
| S-EPMC11245063 | biostudies-literature
Project description:Disruption of endolysosomal acidification is a hallmark of several neurodevelopmental and neurodegenerative disorders. Impaired acidification causes accumulation of toxic protein aggregates and disrupts neuronal homeostasis, yet the molecular mechanisms regulating endolysosomal pH in neurons remain poorly understood. A critical regulator of lumenal acidification is the vacuolar ATPase (VATPase), a proton pump whose activity depends on dynamic assembly of its V0 and V1 subdomains. In this study, we identify transmembrane protein 184B (TMEM184B) as a novel regulator of endolysosomal acidification in neurons. TMEM184B is an evolutionarily conserved 7-pass transmembrane protein required for synaptic structure and function, and sequence variation in TMEM184B causes neurodevelopmental disorders, but the mechanism for this effect is unknown. We performed proteomic analysis of TMEM184B-interacting proteins and identified enrichment of components involved in endosomal trafficking and function, including the V-ATPase. TMEM184B localizes to early and late endosomes, further supporting a role in the endosomal system. Loss of TMEM184B results in significant reductions in endolysosomal acidification within cultured mouse cortical neurons. This alteration in pH is associated with impaired assembly of the V-ATPase V0 and V1 subcomplexes in the TMEM184B mutant mouse brain, suggesting a mechanism by which TMEM184B promotes flux through the endosomal pathway. Overall, these findings identify a new contributor in maintaining endosomal function and provide a mechanistic basis for disrupted neuronal function in human TMEM184B-associated nervous system disorders.
2025-06-16 | PXD064977 | Pride
Project description:Biallelic UNC5C variants cause a recessive neurodevelopmental disorder with brain anomalies
| PRJNA1447502 | ENA
Project description:Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in heterogeneous disease phenotypes in humans which differ from classic Angelman syndrome. We describe two affected siblings who possess an inherited UBE3AL734S variant that causes a strong gain in UBE3A activity. Unlike previously described cases, these individuals exhibited borderline microcephaly, suggesting the extent of UBE3A gain-of-function can produce neomorphic phenotypes. Here, we characterize a mouse model harboring a strong gain of function variant (Ube3aQ606E) which elevates UBE3A activity 388% above wild type (WT) enzyme levels. We conduct extensive behavioral phenotyping to show that Ube3amQ606E mutants show motor deficits, hypoactivity, and reduced stereotypic behaviors. Brain weights and MRI analysis revealed global microcephaly with a postnatal onset. Proteomic analysis performed on neonatal cortex revealed perturbations in several key proteins and pathways linked to neurodevelopmental disease. Finally, we show that microcephaly is not caused by increased apoptotic cell death. Together, our results provide strong evidence that the type and severity of disease phenotypes depend on the causative UBE3A gain of function mutation and provide new insights into the phenotypic heterogeneity observed in individuals with UBE3A gain of function variants.
2025-05-07 | PXD055901 | Pride
Project description:Precise axon guidance is fundamental to neural circuit formation, yet the full spectrum of neurodevelopmental disorders arising from disruptions in this process remains undefined. Here, we describe a multi-ethnic cohort of eight patients from five independent families presenting with a neurodevelopmental disorder characterized by structural brain anomalies, distal limb contractures, developmental delay, intellectual disability, and additional variable features. All affected individuals carry biallelic deleterious variants in UNC5C, a gene encoding a conserved netrin receptor essential for axon guidance and neuronal migration. To investigate the functional consequences of these variants, we performed structural analyses, which indicated that the identified variants disrupt key functional domains, including the immunoglobulin-like (Ig), thrombospondin-1 type repeats (TSP), ZU5, UPA, and death domains. We then introduced disease-associated mutations into conserved residues of the Caenorhabditis elegans unc-5 orthologue using CRISPR/Cas9 genome editing and assessed phenotypic outcomes in vivo. Cell-type-specific rescue experiments revealed the observed motor defects are primarily neurogenic in origin. Consistent with the clinical features observed in patients, C. elegans carrying the corresponding human mutations exhibited defects in axon guidance, locomotion, and behaviour, supporting disruption of UNC-5–mediated signalling pathways. Together, our findings establish biallelic pathogenic variants in UNC5C as the cause of a previously unrecognized autosomal recessive neurodevelopmental disorder with structural brain anomalies and distal limb contractures. Our combined approach of human genetics and in vivo modelling defines a critical role for UNC5C in human neurodevelopment and expands the spectrum of disorders arising from disrupted axon guidance machinery.
2026-04-10 | GSE326863 | GEO
Project description:The goal of this study was to evaluate gene expression that is dependent upon Tmem184b expression. Our objective was to identify pathways controlled by Tmem184b that may influence development or behavior of neurons.
2020-07-14 | GSE154316 | GEO
Project description:Biallelic inactivating variants in the chromatin remodeler DMAP1 cause a syndromic neurodevelopmental disorder
| PRJNA1446757 | ENA
Project description:Variants in ZFX Cause an X-linked Neurodevelopmental Disorder with Recurrent Facial Gestalt
| PRJNA904808 | ENA
Project description:Variants in ZFX Cause an X-linked Neurodevelopmental Disorder with Recurrent Facial Gestalt
| PRJNA904810 | ENA