Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability

Francesca Mattioli, Bertrand Isidor, Omar Abdul-Rahman, Andrew Gunter, Lijia Huang, Raman Kumar, Chandree Beaulieu, Jozef Gecz, Micheil Innes, Jean Louis Mandel, Amelie Piton

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

THOC6 encodes a subunit of the THO complex that is part of a highly conserved transcription and export complex known to have roles in mRNA processing and export. Few homozygous or compound heterozygous variants have been identified in the THOC6 gene in patients with a syndromic form of intellectual disability [Beaulieu-Boycott-Innes syndrome (BBIS); MIM: 613680]. Here we report two additional individuals affected with BBIS originating from the north of Europe and sharing a haplotype composed of three very rare missense changes in the THOC6 gene-Trp100Arg, Val234Leu, Gly275Asp. The first individual is a boy who is homozygous for the three-variant haplotype due to a maternal uniparental disomy event. The second is a girl who is compound heterozygous for this haplotype and a previously reported Gly190Glu missense variant.We analyzed the impact of these different amino acid changes on THOC6 protein expression, cellular localization and interaction with the other THO complex subunits.We show that the different THOC6 variants alter the physiological nuclear localization.

Original languageEnglish (US)
Pages (from-to)952-960
Number of pages9
JournalHuman Molecular Genetics
Volume28
Issue number6
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Mattioli, F., Isidor, B., Abdul-Rahman, O., Gunter, A., Huang, L., Kumar, R., Beaulieu, C., Gecz, J., Innes, M., Mandel, J. L., & Piton, A. (2019). Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability. Human Molecular Genetics, 28(6), 952-960. https://doi.org/10.1093/hmg/ddy391