A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex

Am J Hum Genet. 2016 May 5;98(5):909-918. doi: 10.1016/j.ajhg.2016.03.014. Epub 2016 Apr 28.

Abstract

The proteins encoded by TELO2, TTI1, and TTI2 interact to form the TTT complex, a co-chaperone for maturation of the phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Here we report six affected individuals from four families with intellectual disability (ID) and neurological and other congenital abnormalities associated with compound heterozygous variants in TELO2. Although their fibroblasts showed reduced steady-state levels of TELO2 and the other components of the TTT complex, PIKK functions were normal in cellular assays. Our results suggest that these TELO2 missense variants result in loss of function, perturb TTT complex stability, and cause an autosomal-recessive syndromic form of ID.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Carrier Proteins / genetics
  • Child
  • Female
  • Humans
  • Intellectual Disability / etiology*
  • Male
  • Molecular Chaperones / genetics*
  • Pedigree
  • Phosphatidylinositol 3-Kinases / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Telomere-Binding Proteins / genetics*

Substances

  • Carrier Proteins
  • Molecular Chaperones
  • TTI2 protein, human
  • Telomere-Binding Proteins
  • Tti1 protein, human
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases