Intellectual disability associated with a homozygous missense mutation in THOC6
Authors:
- Chandree L BeaulieuCBChandree L Beaulieu
- Lijia HuangLHLijia Huang
- A Micheil InnesAIA Micheil Innes
- Marie-Andree AkimenkoMAMarie-Andree Akimenko
- Erik G PuffenbergerEPErik G Puffenberger
- Charles SchwartzCSCharles Schwartz
- Paul JerryPJPaul Jerry
- Carole OberCOCarole Ober
- Robert A HegeleRHRobert A Hegele
- D Ross McLeodDMD Ross McLeod
- Jeremy SchwartzentruberJSJeremy Schwartzentruber
Open Access
- 26 April 2013
- journal article
- Published by Springer Nature in Orphanet Journal of Rare Diseases
- Vol. 8 (1) , 62
Abstract
Background: We recently described a novel autosomal recessive neurodevelopmental disorder with intellectual disability in four patients from two related Hutterite families. Identity-by-descent mapping localized the gene to a 5.1 Mb region at chromosome 16p13.3 containing more than 170 known or predicted genes. The objective of this study was to identify the causative gene for this rare disorder.Methods and results: Candidate gene sequencing followed by exome sequencing identified a homozygous missense mutation p.Gly46Arg, inTHOC6. No other potentially causative coding variants were present within the critical region on chromosome 16. THOC6 is a member of the THO/TREX complex which is involved in coordinating mRNA processing with mRNA export from the nucleus.In situhybridization showed thatthoc6is highly expressed in the midbrain and eyes. Cellular localization studies demonstrated that wild-type THOC6 is present within the nucleus as is the case for other THO complex proteins. However, mutant THOC6 was predominantly localized to the cytoplasm, suggesting that the mutant protein is unable to carry out its normal function. siRNA knockdown ofTHOC6revealed increased apoptosis in cultured cells.Conclusion: Our findings associate a missense mutation inTHOC6with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.Keywords
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