2. Academic Validation
  3. A homozygous founder mutation in TRAPPC6B associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features

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

  • J Med Genet. 2018 Jan;55(1):48-54. doi: 10.1136/jmedgenet-2017-104627.
Isaac Marin-Valencia 1,  Gaia Novarino 1 2,  Anide Johansen 3 4,  Basak Rosti 1 3 4,  Mahmoud Y Issa 5,  Damir Musaev 3 4,  Gifty Bhat 1,  Eric Scott 3 4,  Jennifer L Silhavy 3 4,  Valentina Stanley 3 4,  Rasim O Rosti 1 3 4,  Jeremy W Gleeson 3 4,  Farhad B Imam 6,  Maha S Zaki 5,  Joseph G Gleeson 1 3 4
Affiliations

Affiliations

  • 1 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA.
  • 2 Institute of Science and Technology Austria (IST), Klosterneuburg, Niederösterreich, Austria.
  • 3 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, La Jolla, California, USA.
  • 4 Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, California, USA.
  • 5 Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  • 6 Department of Pediatrics, University of California, San Diego, California, USA.
PMID: 28626029 DOI: 10.1136/jmedgenet-2017-104627
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.

Keywords

TRAPP complex; TRAPPC6B; autism; epilepsy; intellectual disability; microcephaly.

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