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

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

American Journal of Human Genetics, Volume: 112, Issue: 5, Pages: 1117 - 1138

Swansea University Authors: Anna Powell Orcid Logo, Mark Rees, Seo-Kyung Chung Orcid Logo

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DOI (Published version): 10.1016/j.ajhg.2025.03.015

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 r...

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Published in: American Journal of Human Genetics
ISSN: 0002-9297 1537-6605
Published: Elsevier Inc 2025
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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. 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spelling 2025-05-02T13:20:18.4521501 v2 69406 2025-05-02 Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder b232c310a6c9458e8669feae92e558a0 0000-0002-8581-5262 Anna Powell Anna Powell true false 10f39a4e9c2ee00d453cd84c10667ac8 Mark Rees Mark Rees true false d99cbf3a557e9ee66556dfd95d66a5d8 0000-0002-5008-8384 Seo-Kyung Chung Seo-Kyung Chung true false 2025-05-02 MEDS 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. Journal Article American Journal of Human Genetics 112 5 1117 1138 Elsevier Inc 0002-9297 1537-6605 intellectual disability; neurodevelopmental disorder; zebrafish; disease model; tRNA modification; TRMT1 1 5 2025 2025-05-01 10.1016/j.ajhg.2025.03.015 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee The research in this paper was supported by NIH GM141038 to D.F. Studies performed in the lab of G.K.V. was funded by NIH/ORIP R24OD034438. The clinic-genetic research was funded in part by the Wellcome Trust (WT093205MA and WT104033AIA). This study was funded by the Medical Research Council (MR/S01165X/1, MR/S005021/1, and G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetrees Trust, Ataxia UK, Multiple System Atrophy Trust, Brain Research United Kingdom, Sparks Great Ormond Street Hospital Charity, Muscular Dystrophy United Kingdom (MDUK), Muscular Dystrophy Association (MDA USA), and the King Baudouin Foundation. S.E. and H.H. were supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. B.V. was supported by the Deutsche Forschungsgemeinschaft (DFG) DFG VO 2138/7-1 grant 469177153. J.S. is supported by Cancer Research UK and University College London. A.F. and S.C. were supported by Health & Care Research Wales, Epilepsy Research UK, and Swansea University PhD funding. 2025-05-02T13:20:18.4521501 2025-05-02T13:10:49.3975586 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Stephanie Efthymiou 1 Cailyn P Leo 2 Chenghong Deng 3 Sheng-Jia Lin 4 Reza Maroofian 5 Renee Lin 6 Irem Karagoz 7 Kejia Zhang 8 Rauan Kaiyrzhanov 9 Annarita Scardamaglia 10 Daniel Owrang 11 Valentina Turchetti 12 Friederike Jahnke 13 Kevin Huang 14 Cassidy Petree 15 Anna Powell 0000-0002-8581-5262 16 Mark Rees 17 Javeria Raza Alvi 18 Tipu Sultan 19 Chumei Li 20 Marie-Line Jacquemont 21 Frederic Tran-Mau-Them 22 Maria Valenzuela-Palafoll 23 Rich Sidlow 24 Grace Yoon 25 Michelle M Morrow 26 Deanna Alexis Carere 27 Mary O'Connor 28 Julie Fleischer 29 Erica H Gerkes 30 Chanika Phornphutkul 31 Bertrand Isidor 32 Clotilde Rivier-Ringenbach 33 Christophe Philippe 34 Semra Hiz Kurul 35 Didem Soydemir 36 Bulent Kara 37 Deniz Sunnetci-Akkoyunlu 38 Viktoria Bothe 39 Konrad Platzer 40 Dagmar Wieczorek 41 Margarete Koch-Hogrebe 42 Nils Rahner 43 Ann-Charlotte Thuresson 44 Hans Matsson 45 Carina Frykholm 46 Sevcan Tuğ Bozdoğan 47 Atil Bisgin 48 Nicolas Chatron 49 Gaetan Lesca 50 Sara Cabet 51 Zeynep Tümer 52 Tina D Hjortshøj 53 Gitte Rønde 54 Thorsten Marquardt 55 Janine Reunert 56 Erum Afzal 57 Mina Zamani 58 Reza Azizimalamiri 59 Hamid Galehdari 60 Pardis Nourbakhsh 61 Niloofar Chamanrou 62 Seo-Kyung Chung 0000-0002-5008-8384 63 Mohnish Suri 64 Paul J Benke 65 Maha S Zaki 66 Joseph G Gleeson 67 Daniel G Calame 68 Davut Pehlivan 69 Halil I Yilmaz 70 Alper Gezdirici 71 Aboulfazl Rad 72 Iman Sabri Abumansour 73 Gabriela Oprea 74 Muhammed Burak Bereketoğlu 75 Guillaume Banneau 76 Sophie Julia 77 Jawaher Zeighami 78 Saeed Ashoori 79 Gholamreza Shariati 80 Alireza Sedaghat 81 Alihossein Sabri 82 Mohammad Hamid 83 Sahere Parvas 84 Tajul Arifin Tajudin 85 Uzma Abdullah 86 Shahid Mahmood Baig 87 Wendy K Chung 88 Olga O Glazunova 89 Sigaudy Sabine 90 Huma Arshad Cheema 91 Giovanni Zifarelli 92 Peter Bauer 93 Jai Sidpra 94 Kshitij Mankad 95 Barbara Vona 96 Andrew E Fry 97 Gaurav K Varshney 98 Henry Houlden 99 Dragony Fu 100 69406__34168__968ddcf0ddc14e3aafccddf19ff57aeb.pdf 69406.VOR.pdf 2025-05-02T13:17:09.8268381 Output 6259734 application/pdf Version of Record true © 2025 The Authors. Published by Elsevier Inc. on behalf of American Society of Human Genetics. This is an open access article distributed under the terms of the Creative Commons CC-BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
spellingShingle Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
Anna Powell
Mark Rees
Seo-Kyung Chung
title_short Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
title_full Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
title_fullStr Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
title_full_unstemmed Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
title_sort Bi-allelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a neurodevelopmental disorder
author_id_str_mv b232c310a6c9458e8669feae92e558a0
10f39a4e9c2ee00d453cd84c10667ac8
d99cbf3a557e9ee66556dfd95d66a5d8
author_id_fullname_str_mv b232c310a6c9458e8669feae92e558a0_***_Anna Powell
10f39a4e9c2ee00d453cd84c10667ac8_***_Mark Rees
d99cbf3a557e9ee66556dfd95d66a5d8_***_Seo-Kyung Chung
author Anna Powell
Mark Rees
Seo-Kyung Chung
author2 Stephanie Efthymiou
Cailyn P Leo
Chenghong Deng
Sheng-Jia Lin
Reza Maroofian
Renee Lin
Irem Karagoz
Kejia Zhang
Rauan Kaiyrzhanov
Annarita Scardamaglia
Daniel Owrang
Valentina Turchetti
Friederike Jahnke
Kevin Huang
Cassidy Petree
Anna Powell
Mark Rees
Javeria Raza Alvi
Tipu Sultan
Chumei Li
Marie-Line Jacquemont
Frederic Tran-Mau-Them
Maria Valenzuela-Palafoll
Rich Sidlow
Grace Yoon
Michelle M Morrow
Deanna Alexis Carere
Mary O'Connor
Julie Fleischer
Erica H Gerkes
Chanika Phornphutkul
Bertrand Isidor
Clotilde Rivier-Ringenbach
Christophe Philippe
Semra Hiz Kurul
Didem Soydemir
Bulent Kara
Deniz Sunnetci-Akkoyunlu
Viktoria Bothe
Konrad Platzer
Dagmar Wieczorek
Margarete Koch-Hogrebe
Nils Rahner
Ann-Charlotte Thuresson
Hans Matsson
Carina Frykholm
Sevcan Tuğ Bozdoğan
Atil Bisgin
Nicolas Chatron
Gaetan Lesca
Sara Cabet
Zeynep Tümer
Tina D Hjortshøj
Gitte Rønde
Thorsten Marquardt
Janine Reunert
Erum Afzal
Mina Zamani
Reza Azizimalamiri
Hamid Galehdari
Pardis Nourbakhsh
Niloofar Chamanrou
Seo-Kyung Chung
Mohnish Suri
Paul J Benke
Maha S Zaki
Joseph G Gleeson
Daniel G Calame
Davut Pehlivan
Halil I Yilmaz
Alper Gezdirici
Aboulfazl Rad
Iman Sabri Abumansour
Gabriela Oprea
Muhammed Burak Bereketoğlu
Guillaume Banneau
Sophie Julia
Jawaher Zeighami
Saeed Ashoori
Gholamreza Shariati
Alireza Sedaghat
Alihossein Sabri
Mohammad Hamid
Sahere Parvas
Tajul Arifin Tajudin
Uzma Abdullah
Shahid Mahmood Baig
Wendy K Chung
Olga O Glazunova
Sigaudy Sabine
Huma Arshad Cheema
Giovanni Zifarelli
Peter Bauer
Jai Sidpra
Kshitij Mankad
Barbara Vona
Andrew E Fry
Gaurav K Varshney
Henry Houlden
Dragony Fu
format Journal article
container_title American Journal of Human Genetics
container_volume 112
container_issue 5
container_start_page 1117
publishDate 2025
institution Swansea University
issn 0002-9297
1537-6605
doi_str_mv 10.1016/j.ajhg.2025.03.015
publisher Elsevier Inc
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 1
active_str 0
description 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.
published_date 2025-05-01T14:15:45Z
_version_ 1851040460435357696
score 11.089469

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