Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder

The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants in tRNA-modification enzymes have been implicated in a wide range of human neurodevelopmental and neurological disorders. However, the molecular basis for many of these disorders remains unknown. Here, we describe a comprehensive cohort of 43 individuals from 31 unrelated families with bi-allelic variants in tRNA methyltransferase 1 (TRMT1). These individuals present with a neurodevelopmental disorder universally characterized by developmental delay and intellectual disability, accompanied by variable behavioral abnormalities, epilepsy, and facial dysmorphism. The identified variants include ultra-rare TRMT1 variants, comprising missense and predicted loss-of-function variants, which segregate with the observed clinical pathology. Our findings reveal that several variants lead to mis-splicing and a consequent loss of TRMT1 protein accumulation. Moreover, cells derived from individuals harboring TRMT1 variants exhibit a deficiency in tRNA modifications catalyzed by TRMT1. Molecular analysis reveals distinct regions of TRMT1 required for tRNA-modification activity and binding. Notably, depletion of Trmt1 protein in zebrafish is sufficient to induce developmental and behavioral phenotypes along with gene-expression changes associated with disrupted cell cycle, immune response, and neurodegenerative disorders. Altogether, these findings demonstrate that loss of TRMT1-catalyzed tRNA modifications leads to intellectual disability and provides insight into the molecular underpinnings of tRNA-modification deficiency caused by pathogenic TRMT1 variants.

Authors

Institutions

Publication Details

Journal
The American Journal of Human Genetics
Published
2025-04-16
DOI
https://doi.org/10.1016/j.ajhg.2025.03.015
Citations
6
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
4.84

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder

Marie‐Line Jacquemont, Chanika Phornphutkul, Seo‐Kyung Chung, Gaurav K. Varshney et al.
6 citations
The American Journal of Human Genetics
RNA modifications and cancer
4.84
article

Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder

Marie‐Line Jacquemont, Chanika Phornphutkul, Seo‐Kyung Chung, Gaurav K. Varshney, Annarita Scardamaglia, Frédéric Tran Mau‐Them, Sophie Julia, Joseph G. Gleeson, Maha Saad Zaki, Irene Valenzuela, Bülent Kara, Zeynep Tümer, Mohammad Hamid, Davut Pehli̇van, Gabriela E. Oprea, Mina Zamani, Stéphanie Efthymiou, Hamid Galehdari, Valentina Turchetti, Anna V. Derrick, Didem Soydemir, Nils Rahner, Sabine Sigaudy, Andrew E. Fry, Ann‐Charlotte Thuresson, Janine Reunert, Christophe Philippe, Sevcan Tuğ Bozdoğan, Sheng‐Jia Lin, Julie Fleischer, Dagmar Wieczorek, Deanna Alexis Carere, Daniel G. Calame, Barbara Vona, Huma Arshad Cheema, Alireza Sedaghat, Erum Afzal, Sara Cabet, Erica H. Gerkes, Iman Sabri Abumansour, Gaëtan Lesca, Dragony Fu, M. Ali Bereketoğlu, Grace Yoon, Javeria Raza Alvi, Mark I. Rees, Olga O. Glazunova, Michelle M. Morrow, Konrad Platzer, Bertrand Isidor, Carina Frykholm, Atıl Bişgin, Deniz Sunnetci‐Akkoyunlu, Chumei Li, Jawaher Zeighami, Giovanni Zifarelli, Kshitij Mankad, Viktoria Bothe, Shahid Mahmood Baig, Gitte Rønde, Uzma Abdullah, Thorsten Marquardt, Abolfazl Rad, Margarete Koch‐Hogrebe, Henry Houlden, Anjum Nasim Sabri, Cassidy Petree, Alper Gezdirici, Gholamreza Shariati, Semra Hız Kurul, Peter Bauer, Jai Sidpra, Hans Matsson, Nicolas Chatron, Sahere Parvas, Reza Maroofian, Clotilde Rivier-Ringenbach, Niloofar Chamanrou, Daniel Owrang, Kejia Zhang, Tipu Sultan, Kevin Huang, Tina Duelund Hjortshøj, Guillaume Banneau, Reza Azizimalamiri, Mohnish Suri, Rauan Kaiyrzhanov, Wendy K. Chung, Friederike Jahnke, Rich Sidlow, Irem Karagoz, Cailyn P Leo, Mary OʼConnor, Renee Lin, Paul J. Benke, Chenghong Deng, Halil Ibrahim Yilmaz, Pardis Nourbakhsh, Saeed Ashoori, Tajul Arifin Tajudin
article en
6 citations

Abstract

The post-transcriptional modification of tRNAs plays a crucial role in tRNA structure and function. Pathogenic variants in tRNA-modification enzymes have been implicated in a wide range of human neurodevelopmental and neurological disorders. However, the molecular basis for many of these disorders remains unknown. Here, we describe a comprehensive cohort of 43 individuals from 31 unrelated families with bi-allelic variants in tRNA methyltransferase 1 (TRMT1). These individuals present with a neurodevelopmental disorder universally characterized by developmental delay and intellectual disability, accompanied by variable behavioral abnormalities, epilepsy, and facial dysmorphism. The identified variants include ultra-rare TRMT1 variants, comprising missense and predicted loss-of-function variants, which segregate with the observed clinical pathology. Our findings reveal that several variants lead to mis-splicing and a consequent loss of TRMT1 protein accumulation. Moreover, cells derived from individuals harboring TRMT1 variants exhibit a deficiency in tRNA modifications catalyzed by TRMT1. Molecular analysis reveals distinct regions of TRMT1 required for tRNA-modification activity and binding. Notably, depletion of Trmt1 protein in zebrafish is sufficient to induce developmental and behavioral phenotypes along with gene-expression changes associated with disrupted cell cycle, immune response, and neurodegenerative disorders. Altogether, these findings demonstrate that loss of TRMT1-catalyzed tRNA modifications leads to intellectual disability and provides insight into the molecular underpinnings of tRNA-modification deficiency caused by pathogenic TRMT1 variants.

The American Journal of Human GeneticsVol. 112(5)
Université Claude Bernard Lyon 1 (FR), Ahvaz Jundishapur University of Medical Sciences (IR), Uppsala University (SE), University of Copenhagen (DK), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Pasteur Institute of Iran (IR), National Institute for Biotechnology and Genetic Engineering (PK), Children’s Institute (US), Nottingham University Hospitals NHS Trust (GB), University Medical Center Groningen (NL), Pakistan Institute of Engineering and Applied Sciences (PK), Harvard University (US), Inserm (FR), Punjab Institute of Cardiology (PK), Wellcome Centre for Human Neuroimaging (GB), Université de Bourgogne (FR), Baylor College of Medicine (US), University of Toronto (CA), Dokuz Eylül University (TR), Shahid Chamran University of Ahvaz (IR), Southern Illinois University School of Medicine (US), Pir Mehr Ali Shah Arid Agriculture University (PK), University of Münster (DE), Brown University (US), Great Ormond Street Hospital (GB), University Hospital of Wales (GB), Hospital for Sick Children (CA), Herlev Hospital (DK), Copenhagen University Hospital (DK), Rigshospitalet (DK), Nottingham City Hospital (GB), University of Health Sciences Lahore (PK), Centre Hospitalier Universitaire de Nantes (FR), Oklahoma Medical Research Foundation (US), Sultan Ismail Specialist Hospital (MY), Swansea University (GB), Ege University (TR), Hôpital Femme Mère Enfant (FR), Méditerranée Infection Foundation (FR), Biotechnology Research Center (IR), Düsseldorf University Hospital (DE), Vestische Caritas-Kliniken (DE), Kennedy Center (DK), Centre de Recherche en Neurosciences de Lyon (FR), King Abdullah International Medical Research Center (SA), Centre For Human Genetics (IN), Vall d'Hebron Institut de Recerca (ES), Istanbul Metropolitan Municipality (TR), Children's Hospital Central California (US), Hasbro Children's Hospital (US), Laboratoire National de Référence (MA), Hôpital Nord (FR), CHU Dijon Bourgogne (FR), Medical Genetics Center (DE), Universitätsmedizin Göttingen (DE), European Neuroscience Institute Göttingen (DE), Institut NeuroMyoGène (FR), Centogene (Germany) (DE), Institut du Thorax (FR), Texas Children's Hospital (US), National Hospital for Neurology and Neurosurgery (GB), Joe DiMaggio Children's Hospital (US), Intergen (Turkey) (TR), İstanbul Başakşehir Çam ve Sakura Şehir Hastanesi, Heinrich Heine University Düsseldorf (DE), University College London (GB), Kocaeli Üniversitesi (TR), University of Rochester (US), Cukurova University (TR), University of Göttingen (DE), Leipzig University (DE), McMaster University (CA)
Muscular Dystrophy Association, Wellcome Trust, Muscular Dystrophy UK, Cancer Research UK, National Institute for Health and Care Research, Epilepsy Research UK, Ataxia UK, University College London, Rosetrees Trust, Great Ormond Street Hospital Charity, Swansea University, Deutsche Forschungsgemeinschaft, Koning Boudewijnstichting, National Institutes of Health, Medical Research Council, Office of Research Infrastructure Programs, National Institutes of Health
Zero hunger
Openalex Percentile: Top 5%
RNA modifications and cancer
4.84
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.