American journal of human genetics · 2025

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

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

Аннотация

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.

Предметные рубрики MeSH

Humans RNA, Transfer Neurodevelopmental Disorders tRNA Methyltransferases Animals Male Zebrafish Female Alleles Child Child, Preschool Intellectual Disability RNA Processing, Post-Transcriptional Adolescent

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

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Аннотация

Предметные рубрики MeSH