2. Academic Validation
  3. A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex

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.
Jing You 1,  Nara L Sobreira 2,  Dustin L Gable 3,  Julie Jurgens 1,  Dorothy K Grange 4,  Newell Belnap 5,  Ashley Siniard 5,  Szabolcs Szelinger 5,  Isabelle Schrauwen 5,  Ryan F Richholt 5,  Stephanie E Vallee 6,  Mary Beth P Dinulos 7,  David Valle 8,  Mary Armanios 9,  Julie Hoover-Fong 10
Affiliations

Affiliations

  • 1 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 2 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 3 Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 4 Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • 5 Translational Genomics Research Institute (TGen) Center for Rare Childhood Disorders, Phoenix, AZ 85004, USA; Neurogenomics Division, Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA.
  • 6 Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr., Lebanon, NH 03756, USA.
  • 7 Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr., Lebanon, NH 03756, USA; Pediatrics and Pathology Department, Geisel School of Medicine at Dartmouth, 1 Medical Center Dr., Lebanon, NH 03756, USA.
  • 8 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: [email protected].
  • 9 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 10 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
PMID: 27132593 DOI: 10.1016/j.ajhg.2016.03.014
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.

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