A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features Journal Article


Author(s): Marin-Valencia, Isaac; Novarino, Gaia; Johansen, Anide; Rosti, Başak; Issa, Mahmoud Y; Musaev, Damir; Bhat, Gifty; Scott, Eric; Silhavy, Jennifer L; Stanley, Valentina; Rosti, Rasim Ö; Gleeson, Jeremy W; Imam, Farhad B; Zaki, Maha S; Gleeson, Joseph G
Article Title: A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly epilepsy and autistic features
Affiliation IST Austria
Abstract: Background: Transport protein particle (TRAPP) is a multisubunit complex that regulates membrane trafficking through the Golgi apparatus. The clinical phenotype associated with mutations in various TRAPP subunits has allowed elucidation of their functions in specific tissues. The role of some subunits in human disease, however, has not been fully established, and their functions remain uncertain. Objective: We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families. Methods: Linkage and homozygosity mapping and candidate gene analysis were used to identify homozygous mutations in families. Patient fibroblasts were used to study splicing defect and zebrafish to model the disease. Results: We identified six individuals from three unrelated families with a founder homozygous splice mutation in TRAPPC6B, encoding a core subunit of the complex TRAPP I. Patients manifested a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features, and showed splicing defect. Zebrafish trappc6b morphants replicated the human phenotype, displaying decreased head size and neuronal hyperexcitability, leading to a lower seizure threshold. Conclusion: This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.
Journal Title: Journal of Medical Genetics
Volume: 55
ISSN: 1468-6244
Publisher: BMJ Publishing Group  
Date Published: 2018-01-01
Start Page: 48
End Page: 54
DOI: 10.1136/jmedgenet-2017-104627
Notes: Funding: IM–V was sponsored by Pilot Grant awarded by the Center for Basic and Translational Research on Disorders of the Digestive System at The Rockefeller University through the generosity of the Leona M and Harry B. Helmsley Charitable Trust. The authors thank the Broad Institute and Yale Mendelian Sequencing Effort. They thank the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur) and the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel). This work was supported by NIH grants P01HD070494, R01NS048453, R01NS052455, P01HD070494, the Simons Foundation Autism Research Initiative and Howard Hughes Medical Institute (to JGG and GN).
Open access: no