In this thesis, I focus on TRAPPC2L, a recently discovered core subunit of the TRAnsport Particle Protein (TRAPP) complexes, which is not well studied. I performed biochemical and cell biological functional studies to characterize the cellular phenotype of the first identified
homozygous missense variants (p.Asp37Tyr and p.Ala2Gly) in TRAPPC2L linked to neurodevelopmental delays and intellectual disabilities. In this study, I show that only the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction betweenTRAPPC2L and TRAPPC6a, another core TRAPP protein. I also show by using size exclusion chromatography that both TRAPPC2L variants disrupted the assembly and stability of the TRAPP complexes in lysates from fibroblasts harbouring the two variants. In addition, we used two different membrane trafficking assays on fibroblasts from individuals harboring
the variants in TRAPPC2L and we found delays in endoplasmic reticulum-to-Golgi and post-Golgi trafficking. In this study, I better characterized the role of TRAPPC2L in the function and assembly of TRAPP and supported the pathogenicity of the two TRAPPC2L variants, p.(Asp37Tyr) and p.(Ala2Gly).