TY - JOUR
T1 - Intellectual disability associated with a homozygous missense mutation in THOC6
AU - Beaulieu, Chandree L.
AU - Huang, Lijia
AU - Innes, A. Micheil
AU - Akimenko, Marie Andree
AU - Puffenberger, Erik G.
AU - Schwartz, Charles
AU - Jerry, Paul
AU - Ober, Carole
AU - Hegele, Robert A.
AU - McLeod, D. Ross
AU - Schwartzentruber, Jeremy
AU - Majewski, Jacek
AU - Bulman, Dennis E.
AU - Parboosingh, Jillian S.
AU - Boycott, Kym M.
N1 - Funding Information:
We would like to thank the patients and their families for participation. We thank Jackie Morris and Carol Farr for clinical support and Dr. Amanda Smith and Jing Zhang for technical support. We thank Dr. Robin Reed for helpful discussions on the THO/TREX complex. The authors wish to acknowledge the contribution of the high throughput sequencing platform of the McGill University and Génome Québec Innovation Centre, Montréal, Canada. This work was supported in part by research grant #5-FY09-529 from the March of Dimes Foundation and by the Government of Canada through the FORGE (Finding of Rare Disease Genes) Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research and the Ontario Genomics Institute (OGI-049). Additional funding to FORGE was provided by Genome Quebec, Genome British Columbia, and the McLaughlin Centre. C.S. received funding from the South Carolina Department of Disabilities and Special Needs. J.S.P. received funding from Alberta Children’s Hospital Foundation. K.M.B. is supported by a Clinical Investigatorship Award from the Canadian Institutes of Health Research, Institute of Genetics. This work was selected by the FORGE Canada Consortium Steering Committee: Kym Boycott (leader; University of Ottawa), Jan Friedman (co-lead; University of British Columbia), Jacques Michaud (co-lead; Université de Montréal), Francois Bernier (University of Calgary), Michael Brudno (University of Toronto), Bridget Fernandez (Memorial University), Bartha Knoppers (McGill University), Mark Samuels (Université de Montréal), Steve Scherer (University of Toronto).
PY - 2013
Y1 - 2013
N2 - 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, in THOC6. 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 situ hybridization showed that thoc6 is 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 of THOC6 revealed increased apoptosis in cultured cells. Conclusion: Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.
AB - 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, in THOC6. 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 situ hybridization showed that thoc6 is 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 of THOC6 revealed increased apoptosis in cultured cells. Conclusion: Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.
KW - Hutterite
KW - Intellectual disability
KW - THO/TREX complex
KW - THOC6
KW - mRNA export
UR - http://www.scopus.com/inward/record.url?scp=84876680733&partnerID=8YFLogxK
U2 - 10.1186/1750-1172-8-62
DO - 10.1186/1750-1172-8-62
M3 - Journal Article
C2 - 23621916
AN - SCOPUS:84876680733
VL - 8
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 62
ER -