Περίληψη:
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. © 2023 American Society of Human Genetics
Συγγραφείς:
Serey-Gaut, M.
Cortes, M.
Makrythanasis, P.
Suri, M.
Taylor, A.M.R.
Sullivan, J.A.
Asleh, A.N.
Mitra, J.
Dar, M.A.
McNamara, A.
Shashi, V.
Dugan, S.
Song, X.
Rosenfeld, J.A.
Cabrol, C.
Iwaszkiewicz, J.
Zoete, V.
Pehlivan, D.
Akdemir, Z.C.
Roeder, E.R.
Littlejohn, R.O.
Dibra, H.K.
Byrd, P.J.
Stewart, G.S.
Geckinli, B.B.
Posey, J.
Westman, R.
Jungbluth, C.
Eason, J.
Sachdev, R.
Evans, C.-A.
Lemire, G.
VanNoy, G.E.
O'Donnell-Luria, A.
Mau-Them, F.T.
Juven, A.
Piard, J.
Nixon, C.Y.
Zhu, Y.
Ha, T.
Buckley, M.F.
Thauvin, C.
Essien Umanah, G.K.
Van Maldergem, L.
Lupski, J.R.
Roscioli, T.
Dawson, V.L.
Dawson, T.M.
Antonarakis, S.E.
