Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
American journal of human genetics
Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.
Serey-Gaut, Margaux; Cortes, Marisol; Makrythanasis, Periklis; Suri, Mohnish; Taylor, Alexander M R; Sullivan, Jennifer A; Asleh, Ayat N; Mitra, Jaba; Dar, Mohamad A; McNamara, Amy; Shashi, Vandana; Dugan, Sarah; Song, Xiaofei; Rosenfeld, Jill A; Cabrol, Christelle; Iwaszkiewicz, Justyna; Zoete, Vincent; Pehlivan, Davut; Akdemir, Zeynep Coban; Roeder, Elizabeth R; Littlejohn, Rebecca Okashah; Dibra, Harpreet K; Byrd, Philip J; Stewart, Grant S; Geckinli, Bilgen B; Posey, Jennifer; Westman, Rachel; Jungbluth, Chelsy; Eason, Jacqueline; Sachdev, Rani; Evans, Carey-Anne; Lemire, Gabrielle; VanNoy, Grace E; O'Donnell-Luria, Anne; Mau-Them, Frédéric Tran; Juven, Aurélien; Piard, Juliette; Nixon, Cheng Yee; Zhu, Ying; Ha, Taekjip; Buckley, Michael F; Thauvin, Christel; Essien Umanah, George K; Van Maldergem, Lionel; Lupski, James R; Roscioli, Tony; Dawson, Valina L; Dawson, Ted M; and Antonarakis, Stylianos E, "Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly." (2023). Articles, Abstracts, and Reports. 7084.