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

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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.

authors

  • 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

publication date

  • May 1, 2025