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

TitleA homozygous founder mutation in associates with a neurodevelopmental disorder characterised by microcephaly, epilepsy and autistic features.
Publication TypeJournal Article
Year of Publication2018
AuthorsMarin-Valencia, I, Novarino, G, Johansen, A, Rosti, B, Issa, MY, Musaev, D, Bhat, G, Scott, E, Silhavy, JL, Stanley, V, Rosti, RO, Gleeson, JW, Imam, FB, Zaki, MS, Gleeson, JG
JournalJ Med Genet
Volume55
Issue1
Pagination48-54
Date Published2018 Jan
ISSN1468-6244
KeywordsAnimals, Autistic Disorder, Epilepsy, Founder Effect, Genetic Association Studies, Homozygote, Humans, Microcephaly, Mutation, Neurodevelopmental Disorders, Phenotype, Vesicular Transport Proteins, Zebrafish
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 , 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 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 in brain development and function.

DOI10.1136/jmedgenet-2017-104627
Alternate JournalJ. Med. Genet.
PubMed ID28626029
PubMed Central IDPMC6056005
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R24 DK080506 / DK / NIDDK NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
K08 HL134579 / HL / NHLBI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States