Publication: Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly
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Date
2023-03-01
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Abstract
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) en-cephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal micro-cephaly, 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.
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Tıp, Dahili Tıp Bilimleri, Tıbbi Genetik, Yaşam Bilimleri, Moleküler Biyoloji ve Genetik, Sağlık Bilimleri, Temel Bilimler, Medicine, Internal Medicine Sciences, Medical Genetics, Life Sciences, Molecular Biology and Genetics, Health Sciences, Natural Sciences, GENETİK VE KALITIM, Yaşam Bilimleri (LIFE), GENETICS & HEREDITY, MOLECULAR BIOLOGY & GENETICS, Life Sciences (LIFE), Genetik (klinik), Moleküler Biyoloji, Genetik, Genetics (clinical), Molecular Biology, Genetics
Citation
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., et al., "Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly", AMERICAN JOURNAL OF HUMAN GENETICS, cilt.110, sa.3, ss.499-515, 2023