THOC6 intellectual disability syndrome is an autosomal recessive neurodevelopmental disorder with intellectual disability of the THOC6 gene localized at chromosome 16p13.3. Initially reported in the Hutterite population, THOC6 intellectual disability syndrome has now been identified in individuals worldwide. This disorder was more prevalent in two Hutterite leuts, with a specific founder variant (c.136G>A;p.Gly46Arg) frequency of 3% in Dariusleut controls and of 2% in Lehrerleut controls.
THOC6 is a part of the THO complex which is involved in coordinating mRNA processing with export. It was demonstrated that the p.Gly46Arg substitution results in protein mislocalization to the cytoplasm suggesting that the mutant protein is unable to carry out an export function. Moreover, depletion of THOC6 induces apoptosis in mammalian cells. These findings indicate that the THOC6 missense mutation perturbs protein function, supporting a disease-association between THOC6 and intellectual disability and an important role for the THO/TREX complex in neurodevelopment.
Mattioli F. et al described two north European individuals carrying the same haplotype in the THOC6 gene, which is composed of three different nucleotide substitutions leading to three missense changes, Trp100Arg, Val234Leu, Gly275Asp, either at the homozygous state or as a compound heterozygous with another missense change, and Gly190Glu. They hypothed that these homozygous variants were originated from a maternal uniparental disomy of chromosome 16. An SNP-array analysis was performed on the proband and confirmed the existence of two different regions of homozygosity, with the following approximate coordinates: chr16: 1-16,227,147 and chr16: 84,453,753-90,354,753. They demonstrated that this haplotype, as well as two other recurrent variants identified in non-consanguineous European population, the truncating Arg87∗ and the missense Gly190Glu variants, alter THOC6 physiological nuclear localization and its interaction with other members of the THO complex, THOC1 and THOC5. The pathogenicity of the haplotype therefore results from a combined effect of at least two of the three missense changes.
THOC6