Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
Détails
ID Serval
serval:BIB_B28CF90D8096
Type
Article: article d'un périodique ou d'un magazine.
Sous-type
Synthèse (review): revue aussi complète que possible des connaissances sur un sujet, rédigée à partir de l'analyse exhaustive des travaux publiés.
Collection
Publications
Institution
Titre
Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
Périodique
American journal of human genetics
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
02/03/2023
Peer-reviewed
Oui
Volume
110
Numéro
3
Pages
499-515
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
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.
Mots-clé
Humans, Intracellular Signaling Peptides and Proteins, Microcephaly, HEK293 Cells, TOR Serine-Threonine Kinases, Neurodevelopmental Disorders, Movement Disorders, TTI1 gene, autosomal recessive, consanguinity, gene, mendelian disorders, microcephaly, neurodevelopment, pathogenic variants
Pubmed
Web of science
Création de la notice
13/02/2023 17:36
Dernière modification de la notice
13/10/2023 6:01