1 Department of Biology, Concordia University, Montreal, Quebec, Canada.
2 Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.
3 Center for Mendelian Genomics, Broad Institute Harvard, Cambridge, Massachusetts, USA.
4 Department of Biomedical Sciences, Columbia University Medical Center, New York, New York, USA.
5 Department of Medicine, Columbia University Medical Center, New York, New York, USA.
6 Department of Biology, Concordia University, Montreal, Quebec, Canada mg3560@cumc.columbia.edu michael.sacher@concordia.ca.
7 Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
8 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA mg3560@cumc.columbia.edu michael.sacher@concordia.ca.

A novel homozygous variant in TRAPPC2L results in a neurodevelopmental disorder and disrupts TRAPP complex function.

J Med Genet. 2020 Aug 25; :

Authors: Al-Deri N, Okur V, Ahimaz P, Milev M, Valivullah Z, Hagen J, Sheng Y, Chung W, Sacher M, Ganapathi M

Abstract

BACKGROUND: Next-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.

METHODS: We 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.

RESULTS: A 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.

CONCLUSION: Our 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.

PMID: 32843486 [PubMed - as supplied by publisher]