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

Am J Hum Genet. 2023 Mar 2;110(3):499-515. doi: 10.1016/j.ajhg.2023.01.006. Epub 2023 Jan 31.

Authors

Margaux Serey-Gaut¹, Marisol Cortes², Periklis Makrythanasis³, Mohnish Suri⁴, Alexander M R Taylor⁵, Jennifer A Sullivan⁶, Ayat N Asleh², Jaba Mitra⁷, Mohamad A Dar², Amy McNamara², Vandana Shashi⁶, Sarah Dugan⁸, Xiaofei Song⁹, Jill A Rosenfeld¹⁰, Christelle Cabrol¹¹, Justyna Iwaszkiewicz¹², Vincent Zoete¹³, Davut Pehlivan¹⁴, Zeynep Coban Akdemir¹⁵, Elizabeth R Roeder¹⁶, Rebecca Okashah Littlejohn¹⁶, Harpreet K Dibra⁵, Philip J Byrd⁵, Grant S Stewart⁵, Bilgen B Geckinli¹⁷, Jennifer Posey¹⁸, Rachel Westman⁸, Chelsy Jungbluth⁸, Jacqueline Eason⁴, Rani Sachdev¹⁹, Carey-Anne Evans²⁰, Gabrielle Lemire²¹, Grace E VanNoy²², Anne O'Donnell-Luria²¹, Frédéric Tran Mau-Them²³, Aurélien Juven²³, Juliette Piard¹¹, Cheng Yee Nixon²⁰, Ying Zhu²⁴, Taekjip Ha⁷, Michael F Buckley²⁴, Christel Thauvin²⁵, George K Essien Umanah², Lionel Van Maldergem²⁶, James R Lupski²⁷, Tony Roscioli²⁸, Valina L Dawson²⁹, Ted M Dawson³⁰, Stylianos E Antonarakis³¹

Affiliations

¹ Centre de génétique humaine, Université de Franche-Comté, Besançon, France. Electronic address: sereymargaux@gmail.com.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
⁴ Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁵ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁶ Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
⁷ Department of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
⁸ Providence Medical Group Genetic Clinics, Spokane, WA, USA.
⁹ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
¹⁰ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹¹ Centre de génétique humaine, Université de Franche-Comté, Besançon, France.
¹² Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
¹³ Molecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland; Computer-Aided Molecular Engineering, Department of Oncology, Ludwig Institute for Cancer Research Lausanne Branch, University of Lausanne, Lausanne, Switzerland.
¹⁴ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France.
¹⁵ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; University Texas Health Science Center, Houston, TX 77030, USA.
¹⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁷ Department of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey.
¹⁸ Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
¹⁹ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
²⁰ Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia.
²¹ Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
²² Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
²³ UF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
²⁴ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
²⁵ INSERM UMR1231 GAD, Bourgogne Franche-Comté University, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Dijon-Burgundy University Hospital, Dijon, France.
²⁶ Centre de génétique humaine, Université de Franche-Comté, Besançon, France; Clinical Investigation Center 1431, National Institute of Health and Medical Research (INSERM), CHU, Besancon, France; EA481 Integrative and Cognitive Neuroscience Research Unit, University of Franche-Comte, Besancon, France.
²⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
²⁸ Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Neuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
²⁹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³⁰ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³¹ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland; Medigenome, Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland. Electronic address: stylianos.antonarakis@unige.ch.

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: TTI1 gene; autosomal recessive; consanguinity; gene; mendelian disorders; microcephaly; neurodevelopment; pathogenic variants.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
Microcephaly*
Movement Disorders*
Neurodevelopmental Disorders*
TOR Serine-Threonine Kinases

Substances

Intracellular Signaling Peptides and Proteins
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding