ArticleAmerican journal of human genetics2023
Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
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Article in American journal of human genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed, 5 citations in OpenAlex.
- TTI1 contributes to radioresistance by activating ATM pathway in rectal cancer.Journal of translational medicine · 2025Article
- TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.International journal of molecular sciences · 2023Review
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Authors and funding
49 authors at 16 institutions in 7 countries.
Margaux Serey-GautCentre de génétique humaine, Université de Franche-Comté, Besançon, France. Electronic address: sereymargaux@gmail.com.
Marisol CortesNeuroregeneration 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.
Periklis MakrythanasisService 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.
Mohnish SuriClinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Alexander M R TaylorInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Jennifer A SullivanDepartment of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Ayat N AslehNeuroregeneration 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.
Jaba MitraDepartment of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
Mohamad A DarNeuroregeneration 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.
Amy McNamaraNeuroregeneration 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.
Vandana ShashiDepartment of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Sarah DuganProvidence Medical Group Genetic Clinics, Spokane, WA, USA.
Xiaofei SongDepartment 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.
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Christelle CabrolCentre de génétique humaine, Université de Franche-Comté, Besançon, France.
Justyna IwaszkiewiczMolecular Modeling Group, Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
Vincent ZoeteMolecular 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.
Davut PehlivanDepartment 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.
Zeynep Coban AkdemirHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; University Texas Health Science Center, Houston, TX 77030, USA.
Elizabeth R RoederDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Rebecca Okashah LittlejohnDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Harpreet K DibraInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Philip J ByrdInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Grant S StewartInstitute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Bilgen B GeckinliDepartment of Medical Genetics, Marmara University School of Medicine, Istanbul 34722, Turkey.
Jennifer PoseyDepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Rachel WestmanProvidence Medical Group Genetic Clinics, Spokane, WA, USA.
Chelsy JungbluthProvidence Medical Group Genetic Clinics, Spokane, WA, USA.
Jacqueline EasonClinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Rani SachdevCentre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
Carey-Anne EvansNeuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia.
Gabrielle LemireCenter 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.
Grace E VanNoyCenter for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Anne O'Donnell-LuriaCenter 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.
Frédéric Tran Mau-ThemUF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
Aurélien JuvenUF6254 Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
Juliette PiardCentre de génétique humaine, Université de Franche-Comté, Besançon, France.
Cheng Yee NixonNeuroscience Research Australia (NeuRA) Institute, Sydney, NSW, Australia.
Ying ZhuNew South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Taekjip HaDepartment of Biophysics and Biophysical Chemistry, Biophysics and Biomedical Engineering, JHU Howard Hughes Medical Institute, Baltimore, MD 21205, USA.
Michael F BuckleyNew South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Christel ThauvinINSERM UMR1231 GAD, Bourgogne Franche-Comté University, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Dijon-Burgundy University Hospital, Dijon, France.
George K Essien UmanahNeuroregeneration 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.
Lionel Van MaldergemCentre 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.
James R LupskiDepartment 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.
Tony RoscioliCentre 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.
Valina L DawsonNeuroregeneration 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.
Ted M DawsonNeuroregeneration 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.
Stylianos E AntonarakisDepartment 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.
Baylor College of Medicine · USJohns Hopkins University · USUniversity of Birmingham · GBBroad Institute · USPrince of Wales Hospital · AUProvidence Regional Medical Center Everett · USUniversité de franche-comté · FRDuke Medical Center · USHoward Hughes Medical Institute · USInserm · FRNeuroscience Research Australia · AUNottingham University Hospitals NHS Trust · GBSIB Swiss Institute of Bioinformatics · CHUniversity of Geneva · CHMarmara University · TRSydney Children's Hospital · AU
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MDetermination of the mechanism underlying Thorase modulation of AMPARs mediated neurotransmissionK01NS099362 · NINDS · JOHNS HOPKINS UNIVERSITY · PI UMANAH, GEORGE KWABENA ESSIEN · 2017 to 2019
$689kCancer Research UK C17183/A23303NHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG006542NHGRI NIH HHS UM1 HG008900NINDS NIH HHS K01 NS099362NINDS NIH HHS R35 NS105078
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.
Indexed as
MicrocephalyMovement DisordersNeurodevelopmental DisordersHEK293 CellsHumansIntracellular Signaling Peptides and ProteinsTOR Serine-Threonine KinasesIntracellular Signaling Peptides and ProteinsTOR Serine-Threonine Kinasesautosomal recessiveconsanguinitygenemendelian disordersmicrocephalyneurodevelopmentpathogenic variantsTTI1 gene
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