PUBLICATION

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

Authors
Marin-Valencia, I., Novarino, G., Johansen, A., Rosti, B., Issa, M.Y., Musaev, D., Bhat, G., Scott, E., Silhavy, J.L., Stanley, V., Rosti, R.O., Gleeson, J.W., Imam, F.B., Zaki, M.S., Gleeson, J.G.
ID
ZDB-PUB-170621-9
Date
2017
Source
Journal of Medical Genetics   55(1): 48-54 (Journal)
Registered Authors
Keywords
TRAPP complex, TRAPPC6B, autism, epilepsy, intellectual disability, microcephaly
MeSH Terms
  • Animals
  • Autistic Disorder/complications
  • Autistic Disorder/genetics*
  • Epilepsy/complications
  • Epilepsy/genetics*
  • Founder Effect*
  • Genetic Association Studies*
  • Homozygote
  • Humans
  • Microcephaly/complications
  • Microcephaly/genetics*
  • Mutation/genetics*
  • Neurodevelopmental Disorders/genetics*
  • Phenotype
  • Vesicular Transport Proteins/genetics*
  • Zebrafish
PubMed
28626029 Full text @ J. Med. Genet.
Abstract
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.
We aimed to expand the range of neurodevelopmental disorders associated with mutations in TRAPP subunits by exome sequencing of consanguineous families.
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.
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.
This study provides clinical and functional evidence of the role of TRAPPC6B in brain development and function.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes