A novel homozygous variant in TRAPPC2L results in a neurodevelopmental disorder and disrupts TRAPP complex function
| Autor: | Priyanka Ahimaz, Yufeng Sheng, Jacob J. Hagen, Wendy K. Chung, Michael Sacher, Zaheer Valivullah, Volkan Okur, Mythily Ganapathi, Miroslav P. Milev, Noraldin Al-Deri |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Protein subunit DNA Mutational Analysis Vesicular Transport Proteins Article Structure-Activity Relationship 03 medical and health sciences symbols.namesake 0302 clinical medicine Neurodevelopmental disorder Genetics medicine Humans Missense mutation Genetic Predisposition to Disease Amino Acid Sequence Global developmental delay Age of Onset Alleles Genetic Association Studies Genetics (clinical) Whole genome sequencing biology Homozygote Membrane Transport Proteins Golgi apparatus medicine.disease Phenotype Pedigree 030104 developmental biology TRAPP complex Amino Acid Substitution Haplotypes Neurodevelopmental Disorders Mutation symbols biology.protein Female Protein Multimerization 030217 neurology & neurosurgery Protein Binding Transcription Factors |
| Zdroj: | J Med Genet |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2020-107016 |
| Popis: | BackgroundNext-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in TRAPPC2L, a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis.MethodsWe performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified TRAPPC2L variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein.ResultsA rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in TRAPPC2L was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and in vitro binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11.ConclusionOur data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the TRAPPC2L p.(Ala2Gly) variant. |
| Databáze: | OpenAIRE |
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