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

Abstract

Neurodevelopmental disorder; tRNA modification; Zebrafish

Trastorno del neurodesarrollo; Modificación de ARNt; Pez cebra

Trastorn del neurodesenvolupament; Modificació de tRNA; Peix zebra

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 authors thank the affected individuals and their families for their support of this study. One of the authors of this publication (Z.T.) is a member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, ERN-ITHACA (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). B.V. is a member of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) (EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516). 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.