Mutation in TTI2 reveals a role for triple T complex in human brain development

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. We identified a mutation in TTI2 as a novel cause of autosomal recessive syndromic intellectual disability. TTI2 encodes one of the subunits of the Triple T complex, a regulator of phosphoinositide-3-kinase-related protein kinase (PIKKs) abundance. We demonstrated impaired stability of the Triple T complex and reduced steady-state level of all PIKKs in patient cells. These findings assess the role of TTI2 in the aetiology of intellectual disability and further support the role of PIKK signalling in brain development and functioning. © 2013 WILEY PERIODICALS, INC.