title: A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex.
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.
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: You
authors.affiliation: 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.
authors.forename: Nara L
authors.initials: NL
authors.lastname: Sobreira
authors.affiliation: 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.
authors.forename: Dustin L
authors.initials: DL
authors.lastname: Gable
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Jurgens
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: 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.
authors.forename: Newell
authors.initials: N
authors.lastname: Belnap
authors.affiliation: 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.
authors.forename: Ashley
authors.initials: A
authors.lastname: Siniard
authors.affiliation: 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.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Szelinger
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schrauwen
authors.affiliation: 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.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Richholt
authors.affiliation: Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr., Lebanon, NH 03756, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Vallee
authors.affiliation: 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.
authors.forename: Mary Beth P
authors.initials: MBP
authors.lastname: Dinulos
authors.affiliation: 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: dvalle@jhmi.edu.
authors.forename: David
authors.initials: D
authors.lastname: Valle
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Armanios
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Hoover-Fong
mesh_terms: D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000209:etiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D010375:Pedigree; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D034501:Telomere-Binding Proteins; C552070:TTI2 protein, human; C551530:Tti1 protein, human