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

Margaux Serey-Gaut; Marisol Cortes; Periklis Makrythanasis; Mohnish Suri; Alexander M.R. Taylor; Jennifer A. Sullivan; Ayat N. Asleh; Jaba Mitra; Mohamad A. Dar; Amy McNamara; Vandana Shashi; Sarah Dugan; Xiaofei Song; Jill A. Rosenfeld; Christelle Cabrol; Justyna Iwaszkiewicz; Vincent Zoete; Davut Pehlivan; Zeynep Coban Akdemir; Elizabeth R. Roeder; Rebecca Okashah Littlejohn; Harpreet K. Dibra; Philip J. Byrd; Grant S. Stewart; Bilgen B. Geckinli; Jennifer Posey; Rachel Westman; Chelsy Jungbluth; Jacqueline Eason; Rani Sachdev; Carey Anne Evans; Gabrielle Lemire; Grace E. VanNoy; Anne O'Donnell-Luria; Frédéric Tran Mau-Them; Aurélien Juven; Juliette Piard; Cheng Yee Nixon; Ying Zhu; Taekjip Ha; Michael F. Buckley; Christel Thauvin; George K. Essien Umanah; Lionel Van Maldergem; James R. Lupski; Tony Roscioli; Valina L. Dawson; Ted M. Dawson; Stylianos E. Antonarakis

doi:10.1016/j.ajhg.2023.01.006

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

Margaux Serey-Gaut^*, Marisol Cortes, Periklis Makrythanasis, Mohnish Suri, Alexander M.R. Taylor, Jennifer A. Sullivan, Ayat N. Asleh, Jaba Mitra, Mohamad A. Dar, Amy McNamara, Vandana Shashi, Sarah Dugan, Xiaofei Song, Jill A. Rosenfeld, Christelle Cabrol, Justyna Iwaszkiewicz, Vincent Zoete, Davut Pehlivan, Zeynep Coban Akdemir, Elizabeth R. RoederRebecca Okashah Littlejohn, Harpreet K. Dibra, Philip J. Byrd, Grant S. Stewart, Bilgen B. Geckinli, Jennifer Posey, Rachel Westman, Chelsy Jungbluth, Jacqueline Eason, Rani Sachdev, Carey Anne Evans, Gabrielle Lemire, Grace E. VanNoy, Anne O'Donnell-Luria, Frédéric Tran Mau-Them, Aurélien Juven, Juliette Piard, Cheng Yee Nixon, Ying Zhu, Taekjip Ha, Michael F. Buckley, Christel Thauvin, George K. Essien Umanah, Lionel Van Maldergem, James R. Lupski, Tony Roscioli, Valina L. Dawson, Ted M. Dawson, Stylianos E. Antonarakis^*

^*Corresponding author for this work

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	499-515
Number of pages	17
Journal	American Journal of Human Genetics
Volume	110
Issue number	3
Early online date	31 Jan 2023
DOIs	https://doi.org/10.1016/j.ajhg.2023.01.006
Publication status	Published - 2 Mar 2023

Bibliographical note

Publisher Copyright:
© 2023 American Society of Human Genetics

Keywords

autosomal recessive
consanguinity
gene
mendelian disorders
microcephaly
neurodevelopment
pathogenic variants
TTI1 gene

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2023.01.006

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer
Stewart, G. (Principal Investigator)
Cancer Research Uk
1/09/17 → 31/05/25
Project: Research

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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., Shashi, V., Dugan, S., Song, X., Rosenfeld, J. A., Cabrol, C., Iwaszkiewicz, J., Zoete, V., Pehlivan, D., Akdemir, Z. C., ... Antonarakis, S. E. (2023). Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly. American Journal of Human Genetics, 110(3), 499-515. https://doi.org/10.1016/j.ajhg.2023.01.006

@article{5ae3b5fea8154976b33df4c86b5e45e6,

title = "Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly",

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 = "autosomal recessive, consanguinity, gene, mendelian disorders, microcephaly, neurodevelopment, pathogenic variants, TTI1 gene",

author = "Margaux Serey-Gaut and Marisol Cortes and Periklis Makrythanasis and Mohnish Suri and Taylor, {Alexander M.R.} and Sullivan, {Jennifer A.} and Asleh, {Ayat N.} and Jaba Mitra and Dar, {Mohamad A.} and Amy McNamara and Vandana Shashi and Sarah Dugan and Xiaofei Song and Rosenfeld, {Jill A.} and Christelle Cabrol and Justyna Iwaszkiewicz and Vincent Zoete and Davut Pehlivan and Akdemir, {Zeynep Coban} and Roeder, {Elizabeth R.} and Littlejohn, {Rebecca Okashah} and Dibra, {Harpreet K.} and Byrd, {Philip J.} and Stewart, {Grant S.} and Geckinli, {Bilgen B.} and Jennifer Posey and Rachel Westman and Chelsy Jungbluth and Jacqueline Eason and Rani Sachdev and Evans, {Carey Anne} and Gabrielle Lemire and VanNoy, {Grace E.} and Anne O'Donnell-Luria and Mau-Them, {Fr{\'e}d{\'e}ric Tran} and Aur{\'e}lien Juven and Juliette Piard and Nixon, {Cheng Yee} and Ying Zhu and Taekjip Ha and Buckley, {Michael F.} and Christel Thauvin and {Essien Umanah}, {George K.} and {Van Maldergem}, Lionel and Lupski, {James R.} and Tony Roscioli and Dawson, {Valina L.} and Dawson, {Ted M.} and Antonarakis, {Stylianos E.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Society of Human Genetics",

year = "2023",

month = mar,

day = "2",

doi = "10.1016/j.ajhg.2023.01.006",

language = "English",

volume = "110",

pages = "499--515",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

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Serey-Gaut, M, Cortes, M, Makrythanasis, P, Suri, M, Taylor, AMR, Sullivan, JA, Asleh, AN, Mitra, J, Dar, MA, McNamara, A, Shashi, V, Dugan, S, Song, X, Rosenfeld, JA, Cabrol, C, Iwaszkiewicz, J, Zoete, V, Pehlivan, D, Akdemir, ZC, Roeder, ER, Littlejohn, RO, Dibra, HK, Byrd, PJ, Stewart, GS, Geckinli, BB, Posey, J, Westman, R, Jungbluth, C, Eason, J, Sachdev, R, Evans, CA, Lemire, G, VanNoy, GE, O'Donnell-Luria, A, Mau-Them, FT, Juven, A, Piard, J, Nixon, CY, Zhu, Y, Ha, T, Buckley, MF, Thauvin, C, Essien Umanah, GK, Van Maldergem, L, Lupski, JR, Roscioli, T, Dawson, VL, Dawson, TM & Antonarakis, SE 2023, 'Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly', American Journal of Human Genetics, vol. 110, no. 3, pp. 499-515. https://doi.org/10.1016/j.ajhg.2023.01.006

TY - JOUR

T1 - Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

AU - Serey-Gaut, Margaux

AU - Cortes, Marisol

AU - Makrythanasis, Periklis

AU - Suri, Mohnish

AU - Taylor, Alexander M.R.

AU - Sullivan, Jennifer A.

AU - Asleh, Ayat N.

AU - Mitra, Jaba

AU - Dar, Mohamad A.

AU - McNamara, Amy

AU - Shashi, Vandana

AU - Dugan, Sarah

AU - Song, Xiaofei

AU - Rosenfeld, Jill A.

AU - Cabrol, Christelle

AU - Iwaszkiewicz, Justyna

AU - Zoete, Vincent

AU - Pehlivan, Davut

AU - Akdemir, Zeynep Coban

AU - Roeder, Elizabeth R.

AU - Littlejohn, Rebecca Okashah

AU - Dibra, Harpreet K.

AU - Byrd, Philip J.

AU - Stewart, Grant S.

AU - Geckinli, Bilgen B.

AU - Posey, Jennifer

AU - Westman, Rachel

AU - Jungbluth, Chelsy

AU - Eason, Jacqueline

AU - Sachdev, Rani

AU - Evans, Carey Anne

AU - Lemire, Gabrielle

AU - VanNoy, Grace E.

AU - O'Donnell-Luria, Anne

AU - Mau-Them, Frédéric Tran

AU - Juven, Aurélien

AU - Piard, Juliette

AU - Nixon, Cheng Yee

AU - Zhu, Ying

AU - Ha, Taekjip

AU - Buckley, Michael F.

AU - Thauvin, Christel

AU - Essien Umanah, George K.

AU - Van Maldergem, Lionel

AU - Lupski, James R.

AU - Roscioli, Tony

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Antonarakis, Stylianos E.

PY - 2023/3/2

Y1 - 2023/3/2

N2 - 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.

AB - 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.

KW - autosomal recessive

KW - consanguinity

KW - gene

KW - mendelian disorders

KW - microcephaly

KW - neurodevelopment

KW - pathogenic variants

KW - TTI1 gene

UR - http://www.scopus.com/inward/record.url?scp=85149999518&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2023.01.006

DO - 10.1016/j.ajhg.2023.01.006

M3 - Article

C2 - 36724785

AN - SCOPUS:85149999518

SN - 0002-9297

VL - 110

SP - 499

EP - 515

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 3

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer

Cite this