title: Intellectual disability associated with a homozygous missense mutation in THOC6.
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.
  
  
  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.
  
  
  CONCLUSIONS
  Our findings associate a missense mutation in THOC6 with intellectual disability, suggesting the THO/TREX complex plays an important role in neurodevelopment.
authors.forename: Chandree L
authors.initials: CL
authors.lastname: Beaulieu
authors.forename: Lijia
authors.initials: L
authors.lastname: Huang
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Marie-Andree
authors.initials: MA
authors.lastname: Akimenko
authors.forename: Erik G
authors.initials: EG
authors.lastname: Puffenberger
authors.forename: Charles
authors.initials: C
authors.lastname: Schwartz
authors.forename: Paul
authors.initials: P
authors.lastname: Jerry
authors.forename: Carole
authors.initials: C
authors.lastname: Ober
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.forename: D Ross
authors.initials: DR
authors.lastname: McLeod
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Jillian S
authors.initials: JS
authors.lastname: Parboosingh
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D000818:Animals; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D015027:Zebrafish