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

Details

Serval ID
serval:BIB_B28CF90D8096
Type
Article: article from journal or magazin.
Publication sub-type
Review (review): journal as complete as possible of one specific subject, written based on exhaustive analyses from published work.
Collection
Publications
Institution
Title
Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
Journal
American journal of human genetics
Author(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
Publication state
Published
Issued date
02/03/2023
Peer-reviewed
Oui
Volume
110
Number
3
Pages
499-515
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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) 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.
Keywords
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
Create date
13/02/2023 17:36
Last modification date
13/10/2023 6:01
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