Mutations in the tRNA methyltransferase 1 gene <i>TRMT1</i> cause congenital microcephaly, isolated inferior vermian hypoplasia and cystic leukomalacia in addition to intellectual disability

Blaesius, Kathrin; Abbasi, Ansar Ahmed; Tahir, Tufail Hussain; Tietze, Anna; Picker-Minh, Sylvie; Ali, Ghazanfar; Farooq, Sundas; Hu, Hao; Latif, Zahid; Khan, M. Fahim; Kaindl, Angela M.

doi:10.1002/ajmg.a.38631

Cited by 27 publications

(20 citation statements)

References 13 publications

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“…Notably, exome sequencing studies have implicated frameshift mutations in TRMT1 as the cause for certain forms of autosomal‐recessive intellectual disability (ID) disorders (Blaesius et al, 2018; Davarniya et al, 2015; Monies et al, 2017; Najmabadi et al, 2011). The deletion mutations are predicted to cause frameshifts that result in nonsense‐mediated decay of the messenger RNA transcript and/or truncated proteins lacking the C‐terminal RNA‐binding domain.…”

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An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

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The human TRMT1 gene encodes an RNA methyltransferase enzyme responsible for catalyzing dimethylguanosine (m2,2G) formation in transfer RNAs (tRNAs). Frameshift mutations in TRMT1 have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Here, we describe a homozygous TRMT1 missense variant in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes an arginine residue to a cysteine (R323C) within the methyltransferase domain and is expected to perturb protein folding. Patient cells expressing TRMT1-R323C exhibit a deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss of function. Notably, the TRMT1 R323C mutant retains tRNA binding but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that perturbs tRNA modification activity and demonstrate that m2,2G modifications are disrupted in the cells of patients with TRMT1-associated ID disorders.

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“…Notably, exome sequencing studies have implicated frameshift mutations in TRMT1 as the cause for certain forms of autosomalrecessive intellectual disability (ID) disorders (Blaesius et al, 2018;Davarniya et al, 2015;Monies et al, 2017;Najmabadi et al, 2011).…”

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An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

et al. 2020

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“…The m 2 2 G26 modification was reported to act as a molecular hinge to adjust the tRNA architecture and correlates with the thermostability of specific tRNAs ( 38 , 39 ). Loss-of-function mutations in Trmt1 were reported to be related to neurological diseases ( 40 ). In eukaryotes, tRNA:m 2 G10 is catalyzed by Trmt11 (named as Trm11 in yeast).…”

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confidence: 99%

THUMPD3–TRMT112 is a m2G methyltransferase working on a broad range of tRNA substrates

Yang

Xiong

et al. 2021

Nucleic Acids Research

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Post-transcriptional modifications affect tRNA biology and are closely associated with human diseases. However, progress on the functional analysis of tRNA modifications in metazoans has been slow because of the difficulty in identifying modifying enzymes. For example, the biogenesis and function of the prevalent N2-methylguanosine (m 2 G) at the sixth position of tRNAs in eukaryotes has long remained enigmatic. Herein, using a reverse genetics approach coupled with RNA-mass spectrometry, we identified that THUMP domain-containing protein 3 (THUMPD3) is responsible for tRNA: m 2 G6 formation in human cells. However, THUMPD3 alone could not modify tRNAs. Instead, multifunctional methyltransferase subunit TRM112-like protein (TRMT112) interacts with THUMPD3 to activate its methyltransferase activity. In the in vitro enzymatic assay system, THUMPD3–TRMT112 could methylate all the 26 tested G6-containing human cytoplasmic tRNAs by recognizing the characteristic 3′-CCA of mature tRNAs. We also showed that m 2 G7 of tRNA Trp was introduced by THUMPD3–TRMT112. Furthermore, THUMPD3 is widely expressed in mouse tissues, with an extremely high level in the testis. THUMPD3 -knockout cells exhibited impaired global protein synthesis and reduced growth. Our data highlight the significance of the tRNA: m 2 G6/7 modification and pave a way for further studies of the role of m 2 G in sperm tRNA derived fragments.

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“…Yeast TRM1 and human TRMT1 are encoded in the nucleus, but once expressed, localize to both the nucleus and the mitochondria [47,49]. Defects in m 2,2 G 26 cause temperature sensitivity in yeast [50], and intellectual disability in humans [51][52][53][54]. Additionally, correct pre-tRNA folding in the yeast Schizosaccharomyces pombe was shown to require m 2,2 G 26 modification by Trm1, and/or La RNA chaperone activity [55].…”

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confidence: 99%

Identification of the enzymes responsible for m2,2G and acp3U formation on cytosolic tRNA from insects and plants

et al. 2020

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Posttranscriptional modification of tRNA is critical for efficient protein translation and proper cell growth, and defects in tRNA modifications are often associated with human disease. Although most of the enzymes required for eukaryotic tRNA modifications are known, many of these enzymes have not been identified and characterized in several model multicellular eukaryotes. Here, we present two related approaches to identify the genes required for tRNA modifications in multicellular organisms using primer extension assays with fluorescent oligonucleotides. To demonstrate the utility of these approaches we first use expression of exogenous genes in yeast to experimentally identify two TRM1 orthologs capable of forming N2,N2-dimethylguanosine (m2,2G) on residue 26 of cytosolic tRNA in the model plant Arabidopsis thaliana. We also show that a predicted catalytic aspartate residue is required for function in each of the proteins. We next use RNA interference in cultured Drosophila melanogaster cells to identify the gene required for m2,2G26 formation on cytosolic tRNA. Additionally, using these approaches we experimentally identify D. melanogaster gene CG10050 as the corresponding ortholog of human DTWD2, which encodes the protein required for formation of 3-amino-3-propylcarboxyuridine (acp3U) on residue 20a of cytosolic tRNA. We further show that A. thaliana gene AT2G41750 can form acp3U20b on an A. thaliana tRNA expressed in yeast cells, and that the aspartate and tryptophan residues in the DXTW motif of this protein are required for modification activity. These results demonstrate that these approaches can be used to study tRNA modification enzymes.

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Mutations in the tRNA methyltransferase 1 gene TRMT1 cause congenital microcephaly, isolated inferior vermian hypoplasia and cystic leukomalacia in addition to intellectual disability

Cited by 27 publications

References 13 publications

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

An intellectual disability‐associated missense variant in TRMT1 impairs tRNA modification and reconstitution of enzymatic activity

THUMPD3–TRMT112 is a m2G methyltransferase working on a broad range of tRNA substrates

Identification of the enzymes responsible for m2,2G and acp3U formation on cytosolic tRNA from insects and plants

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