Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Serey-Gaut M., Cortes M., Makrythanasis P., Suri M., Taylor A. M. R., Sullivan J. A., ...Daha Fazla

AMERICAN JOURNAL OF HUMAN GENETICS, cilt.110, sa.3, ss.499-515, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 110 Sayı: 3
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1016/j.ajhg.2023.01.006
  • Dergi Adı: AMERICAN JOURNAL OF HUMAN GENETICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, International Bibliography of Social Sciences, BIOSIS, CAB Abstracts, Chemical Abstracts Core, CINAHL, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.499-515
  • Marmara Üniversitesi Adresli: Evet

Özet

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.