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
Auteur⸱e⸱s
Serey-Gaut M., Cortes M., Makrythanasis P., Suri M., Taylor AMR, 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.
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
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
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