title: Mutation in TTI2 reveals a role for triple T complex in human brain development.
abstract: Tel2-interacting proteins 1 and 2 (TTI1 and TTI2) physically interact with telomere maintenance 2 (TEL2) to form a conserved trimeric complex called the Triple T complex. This complex is a master regulator of phosphoinositide-3-kinase-related protein kinase (PIKKs) abundance and DNA damage response signaling. Using a combination of autozygosity mapping and high-throughput sequencing in a large consanguineous multiplex family, we found that a missense c.1307T>A/p.I436N mutation in TTI2 causes a human autosomal recessive condition characterized by severe cognitive impairment, microcephaly, behavioral troubles, short stature, skeletal anomalies, and facial dysmorphic features. Immunoblotting experiment showed decreased amount of all Triple T complex components in the patient skin fibroblasts. Consistently, a drastically reduced steady-state level of all PIKKs tested was also observed in the patient cells. Combined with previous observations, these findings emphasises the role of the TTI2 gene in the etiology of intellectual disability and further support the role of PIKK signaling in brain development and functioning.
authors: INSERM U781, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
authors: Maéva
authors: M
authors: Langouët
authors: Abdelkrim
authors: A
authors: Saadi
authors: Guillaume
authors: G
authors: Rieunier
authors: Sébastien
authors: S
authors: Moutton
authors: Karine
authors: K
authors: Siquier-Pernet
authors: Marie
authors: M
authors: Fernet
authors: Patrick
authors: P
authors: Nitschke
authors: Arnold
authors: A
authors: Munnich
authors: Marc-Henri
authors: MH
authors: Stern
authors: Malika
authors: M
authors: Chaouch
authors: Laurence
authors: L
authors: Colleaux
mesh_terms: D000328:Adult; D001921:Brain / Q000378:metabolism*; D003241:Consanguinity; D019066:Facies; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011485:Protein Binding; D050783:Proto-Oncogene Proteins c-ets / Q000737:chemistry / Q000378:metabolism
chemical_list: C409823:ETV7 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D050783:Proto-Oncogene Proteins c-ets; C552070:TTI2 protein, human
keywords: PIKK; TTI2; exome sequencing; intellectual disability