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Genes causing microcephaly syndromes. This table contains a summary of selected primary microcephaly syndromes, including MCPH 1-15. Information provided includes a brief description of the phenotype, gene that is mutated, and pathogenic mechanism.
Source publication
Microcephaly is a fairly common feature observed in children with delayed development, defined as head circumference less than 2 standard deviations below the mean for age and gender. It may be the result of an acquired insult to the brain, such prenatal or perinatal brain injury (congenital infection or hypoxic ischemic encephalopathy), or be a pa...
Citations
... tRNAs are among the most heavily modified classes of RNA and these modifications are critical for the stability and translation functionality of tRNAs 11,12 . Mutations of TRMT10A in humans have been linked to primary microcephaly, mild intellectual disability, young onset diabetes, and apoptosis in pancreatic cells [13][14][15][16][17] . However, the mechanisms by which genetic mutations in TRMT10A cause these phenotypes are not well understood. ...
Chronic cellular stress has a profound impact on the brain, leading to degeneration and accelerated aging. Recent work has revealed the vital role of RNA modifications, and the proteins responsible for regulating them, in the stress response. In our study, we defined the role of CG14618/dTrmt10A, the Drosophila counterpart of human TRMT10A a N¹-methylguanosine methyltransferase, on m⁶A regulation and heat stress resilience in the Drosophila brain. By m⁶A-IP RNA sequencing on Drosophila head tissue, we demonstrated that manipulating dTrmt10A levels indirectly regulates m⁶A levels on polyA + RNA. dTrmt10A exerted its influence on m⁶A levels on transcripts enriched for neuronal signaling and heat stress pathways, similar to the m⁶A methyltransferase Mettl3. Intriguingly, its impact primarily targeted 3' UTR m⁶A, setting it apart from the majority of Drosophila m⁶A-modified transcripts which display 5' UTR enrichment. Upregulation of dTrmt10A led to increased resilience to acute heat stress, decreased m⁶A modification on heat shock chaperones, and coincided with decreased decay of chaperone transcripts and increased translation of chaperone proteins. Overall, these findings establish a potential mechanism by which dTrmt10A regulates the acute brain stress response through m⁶A modification.
... The importance of Trm10/TRMT10A has been highlighted by its connection to distinct disease phenotypes. In humans, mutations in the TRMT10A gene are linked to microcephaly and intellectual disability, as well as defects in glucose metabolism (16)(17)(18)(19)(20). Additionally, the S. cerevisiae trm10 deletion strain exhibits hypersensitivity to the anti-tumor drug 5-fluorouracil (21). ...
The methyltransferase Trm10 modifies a subset of tRNAs on the base N1 position of the 9th nucleotide in the tRNA core. Trm10 is conserved throughout Eukarya and Archaea, and mutations in the human gene ( TRMT10A ) have been linked to neurological disorders such as microcephaly and intellectual disability, as well as defects in glucose metabolism. Of the 26 tRNAs in yeast with guanosine at position 9, only 14 are substrates for Trm10. However, no common sequence or other posttranscriptional modifications have been identified among these substrates, suggesting the presence of some other tRNA feature(s) which allow Trm10 to distinguish substrate from nonsubstrate tRNAs. Here, we show that substrate recognition by Saccharomyces cerevisiae Trm10 is dependent on both intrinsic tRNA flexibility and the ability of the enzyme to induce specific tRNA conformational changes upon binding. Using the sensitive RNA structure-probing method SHAPE, conformational changes upon binding to Trm10 in tRNA substrates, but not nonsubstrate, were identified and mapped onto a model of Trm10-bound tRNA. These changes may play an important role in substrate recognition by allowing Trm10 to gain access to the target nucleotide. Our results highlight a novel mechanism of substrate recognition by a conserved tRNA modifying enzyme. Further, these studies reveal a strategy for substrate recognition that may be broadly employed by tRNA-modifying enzymes which must distinguish between structurally similar tRNA species.
... The addition of this modification is nucleo-cytoplasmically performed by the methyltransferase TRMT10A, while in the case of mitochondrial tRNAs (mtRNAs) this is driven by TRM10C (Holzmann et al., 2008). Both writer enzymes are known to have pathogenic mutations: defects in TRMT10A mainly lead to neurodegenerative pathologies and glucose degradation problems (OMIM: 616,033) (Narayanan et al. 2015;Vilardo et al. 2020;Igoillo-Esteve et al. 2013). ...
While the existence of post-transcriptional modifications of RNA nucleotides has been known for decades, in most RNA species the exact positions of these modifications and their physiological function have been elusive until recently. Technological advances, such as high-throughput next-generation sequencing (NGS) methods and nanopore-based mapping technologies, have made it possible to map the position of these modifications with single nucleotide accuracy, and genetic screens have uncovered the “writer”, “reader” and “eraser” proteins that help to install, interpret and remove such modifications, respectively. These discoveries led to intensive research programmes with the aim of uncovering the roles of these modifications during diverse biological processes. In this review, we assess novel discoveries related to the role of post-transcriptional modifications during animal development, highlighting how these discoveries can affect multiple aspects of development from fertilization to differentiation in many species.
... In some patients the microcephaly presented at birth and resolved later and others had persistent microcephaly. Some patients had epilepsy and two patients had abnormal brain MRI findings (6). Another main feature of the syndrome is abnormal glucose homeostasis. ...
A new syndrome of diabetes, short stature, microcephaly and intellectual disability has been described in association with mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene. We report a patient who presented with fasting hyperglycemia, a raised HbA1C and positive islet cell autoantibodies. Additional clinical features included intellectual disability, hypoplastic kidneys and short stature. In view of syndromic features alongside diabetes, genetic evaluation was carried out revealing a homozygous mutation in the TRMT10A gene (c.616G>A, p.G206R). The case highlights the importance of genetic evaluation of patients with diabetes with atypical features that can further progress our understanding of the pathophysiology of the rarer subtypes of diabetes.
... Alterations in tRNA biology have been associated with a large variety of human diseases including cancer, neurological, mitochondrial, and metabolic disorders [7,52,61,[71][72][73][74]. Related to the latter, mutations in aaRSs [75][76][77][78][79][80][81][82] and intronic variants in the tRNAmodifying enzyme CDKAL1 [83][84][85] have been associated with increased risk for T2D and obesity. Mutations in mt-tRNA genes are associated with maternally inherited diabetes and deafness (MIDD) and insulin resistance [86][87][88][89][90] and mutations in the tRNA methyltransferase TRMT10A cause young onset diabetes and microcephaly [53,[91][92][93][94][95][96]. Oxidative stress and iron deficiency have been associated with impaired tRNA modifications and diabetes [97,98], while diet-induced epididymal tRNA methylation and fragmentation were linked with intergenerational inheritance of metabolic traits [30,31,55]. ...
... Homozygous inactivating mutations in the TRMT10A gene cause young onset diabetes, microcephaly, intellectual disability, and epilepsy [91][92][93][94][95][96]. We were the first to report this association in three patients from a consanguineous family of Moroccan origin [91]. ...
... We were the first to report this association in three patients from a consanguineous family of Moroccan origin [91]. This original study was followed by five additional reports from independent research groups that identified nine additional patients from five unrelated families having biallelic nonsense, missense, or deletion mutations in TRMT10A and very similar clinical manifestations [92][93][94][95][96]. TRMT10A is a tRNA methyltransferase with major nuclear localization that catalyses guanosine 9 methylation (m 1 G9) in some cytosolic tRNAs ( Figure 1) [53,91]. ...
The global rise in type 2 diabetes results from a combination of genetic predisposition with environmental assaults that negatively affect insulin action in peripheral tissues and impair pancre-atic β-cell function and survival. Nongenetic heritability of metabolic traits may be an important contributor to the diabetes epidemic. Transfer RNAs (tRNAs) are noncoding RNA molecules that play a crucial role in protein synthesis. tRNAs also have noncanonical functions through which they control a variety of biological processes. Genetic and environmental effects on tRNAs have emerged as novel contributors to the pathogenesis of diabetes. Indeed, altered tRNA aminoacylation, modification , and fragmentation are associated with β-cell failure, obesity, and insulin resistance. Moreover , diet-induced tRNA fragments have been linked with intergenerational inheritance of metabolic traits. Here, we provide a comprehensive review of how perturbations in tRNA biology play a role in the pathogenesis of monogenic and type 2 diabetes.
... 3 A total of 11 cases were subsequently reported. [4][5][6][7] Our case is the 12th one and also the first report in the Asian population. ...
... Our patient's head circumference at birth was not recorded but became obvious as our patient grew, as reported by Igoillo-Esteve et al. 3 All the individuals had intellectual disability, including language development and motor development. In addition, epilepsy was common except the individual reported by Zung et al. 4 The two individuals reported by Narayanan et al 6 had abnormal EEG that showed as symmetric, bilateral, frontally dominant polyspike and wave discharges, consistent with generalized epilepsy, with abnormal brain MRI that showed mild Fluid attenuated inversion Genetics/Genomes/Proteomics/Metabolomics recovery (FLAIR)/T2 hyperintensities in the periatrial white matter, although the EEG and brain imaging of other individuals are normal (or not reported). ...
Introduction
Loss-of-function mutations in tRNA methyltransferase 10 homologue A ( TRMT10A ), a tRNA methyltransferase, have recently been described as a monogenic cause of early-onset diabetes with microcephaly, epilepsy and intellectual disability.
Research design and methods
We report a Chinese young patient who was diagnosed with diabetes mellitus as a result of a TRMT10A mutation.
Results
A homozygous mutation c.496–1G>A in TRMT10A was identified using targeted next-generation sequencing and confirmed by PCR/Sanger sequencing. In addition to being diagnosed with diabetes, the patient also has microcephaly and intellectual deficiency. The diabetes was due to marked insulin resistance and responded very well to metformin treatment.
Conclusion
Our case is the first report in the Asian population. It adds to current knowledge of TRMT10A related with young-onset non-insulin-dependent diabetes and confirms the a single previous report of insulin resistance in this syndrome. Genomic testing should be considered in children with non-insulin-dependent diabetes with intellectual disability and microcephaly. A clear genetic diagnosis is helpful for early detection and treatment addressing insulin resistance.
... Thus, the actual enzymatic specificity of TRMT10B and its function in vivo remain to be elucidated. Remarkably, mutations in the gene of TRMT10A were recently reported to be associated with a severe medical condition characterised by microcephaly and early onset diabetes (15)(16)(17)(18)(19). These findings highlight the need to better understand the function of the members of the human TRM10 enzyme family and their impact on cellular physiology. ...
... We only observed a slight tendency to slower growth in TRMT10A-KO cells; however, it shall be noted that due to the clonal selection of the KO cell lines, a bias toward the selection of faster-growing lines during clone isolation may not be excluded. In humans, loss-of-function mutations in TRMT10A are associated with a severe neurodevelopmental disorder and early-onset diabetes (15)(16)(17)(18). A recent report showed that the depletion of TRMT10A in pancreatic -cell lines causes an accumulation of 5 fragments of tRNA Gln , which was suggested to induce apoptotic cell death (12). ...
The TRM10 family of methyltransferases is responsible for the N1-methylation of purines at position 9 of tRNAs in Archaea and Eukarya. The human genome encodes three TRM10-type enzymes, of which only the mitochondrial TRMT10C was previously characterized in detail, whereas the functional significance of the two presumably nuclear enzymes TRMT10A and TRMT10B remained unexplained. Here we show that TRMT10A is m1G9-specific and methylates a subset of nuclear-encoded tRNAs, whilst TRMT10B is the first m1A9-specific tRNA methyltransferase found in eukaryotes and is responsible for the modification of a single nuclear-encoded tRNA. Furthermore, we show that the lack of G9 methylation causes a decrease in the steady-state levels of the initiator tRNAiMet-CAT and an alteration in its further post-transcriptional modification. Our work finally clarifies the function of TRMT10A and TRMT10B in vivo and provides evidence that the loss of TRMT10A affects the pool of cytosolic tRNAs required for protein synthesis.
... Human TRMT10A was shown installing m 1 G9 in tRNAs in vitro using yeast and human tRNAs as the substrates (18). Mutations in TRMT10A have been observed in patients with young-onset diabetes syndrome and primary microcephaly-mild intellectual disability (14,(19)(20)(21)(22), and recent studies have suggested that deficiency of TRMT10A can induce apoptosis in pancreatic cells, consistent with the correlation with diabetes (14,22). However, the mechanism by which deficiency of TRMT10A is linked to the disease phenotype remains enigmatic. ...
... Previous studies showed G206R, which is a catalytic-inactive variant of TRMT10A, is present in patients with young onset diabetes and primary microcephaly (22). Interestingly, a few other disease-related mutation sites in TRMT10A are found outside of the catalytic domain and are clustered more toward the N-terminal domain (19,62). Data from TCGA database highlights several mutation sites in TRMT10A both inside and outside the catalytic domain of TRMT10A from colorectal cancer patients (63,64). ...
The posttranscriptional modification of messenger RNA (mRNA) and transfer RNA (tRNA) provides an additional layer of regulatory complexity during gene expression. Here, we show that a tRNA methyltransferase, TRMT10A, interacts with an mRNA demethylase FTO (ALKBH9), both in vitro and inside cells. TRMT10A installs N¹ -methylguanosine (m ¹ G) in tRNA, and FTO performs demethylation on N⁶ -methyladenosine (m ⁶ A) and N⁶ ,2′- O -dimethyladenosine (m ⁶ A m ) in mRNA. We show that TRMT10A ablation not only leads to decreased m ¹ G in tRNA but also significantly increases m ⁶ A levels in mRNA. Cross-linking and immunoprecipitation, followed by high-throughput sequencing results show that TRMT10A shares a significant overlap of associated mRNAs with FTO, and these mRNAs have accelerated decay rates potentially through the regulation by a specific m ⁶ A reader, YTHDF2. Furthermore, transcripts with increased m ⁶ A upon TRMT10A ablation contain an overrepresentation of m ¹ G9-containing tRNAs codons read by tRNA Gln(TTG) , tRNA Arg(CCG) , and tRNA Thr(CGT) . These findings collectively reveal the presence of coordinated mRNA and tRNA methylations and demonstrate a mechanism for regulating gene expression through the interactions between mRNA and tRNA modifying enzymes.
... Hypomodification of mitochondrial tRNAs (mt-tRNAs) cause maternally inherited diabetes and deafness (MIDD) (6)(7)(8). Genetic variants or loss-offunction mutations in different tRNA-modifying enzymes are associated with type 2 diabetes and monogenic diabetes (9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Research on these tRNA epitranscriptome perturbations is uncovering fascinating new pathways leading to pancreatic b-cell demise. ...
... Mutations in mitochondrial, nuclear, and cytosolic tRNA-modifying enzymes and mt-tRNAs perturb the tRNA epitrancriptome and cause neurologic disorders, cancer, and metabolic diseases (63,64). Herein, we review metabolic diseases linked to abnormal tRNA modifications and the underlying pathogenic mechanisms [ Fig. 3 (7,(9)(10)(11)(12)(13)(14)(15)(16)(17)(65)(66)(67)(68)(69)(70)(71)]. ...
... Mutations in TRMT10A, a tRNA methyltransferase, cause young-onset diabetes and microcephaly. Eleven patients, from five nonrelated families with different nonsense or missense TRMT10A mutations or TRMT10A deletions, have so far been described (10,(12)(13)(14)(15). Most have primary microcephaly, intellectual disability, and epilepsy and develop diabetes in adolescence or young adulthood (Table 1). ...
tRNAs are crucial noncoding RNA molecules that serve as amino acid carriers during protein synthesis. The transcription of tRNA genes is a highly regulated process. The tRNA pool is tissue and cell specific, it varies during development, and it is modulated by the environment. tRNAs are highly posttranscriptionally modified by specific tRNA-modifying enzymes. The tRNA modification signature of a cell determines the tRNA epitranscriptome. Perturbations in the tRNA epitranscriptome, as a consequence of mutations in tRNAs and tRNA-modifying enzymes or environmental exposure, have been associated with human disease, including diabetes. tRNA fragmentation induced by impaired tRNA modifications or dietary factors has been linked to pancreatic β-cell demise and paternal inheritance of metabolic traits. Herein, we review recent findings that associate tRNA epitranscriptome perturbations with diabetes.
... TRMT10A is a tRNA-methyltransferase that catalyzes methylation of guanine-9 (m 1 G 9 ). Several studies have reported TRMT10A nonsense mutations in young-onset diabetes and microcephaly, which is correlated with its enriched expression in the pancreas and brain [81][82][83][84] (Figure 3; Table 1). Recently, tRNA Gln and tRNA iMet were identified as TRMT10A targets. ...
Transfer RNAs (tRNAs) are key players of protein synthesis, as they decode the genetic information organized in mRNA codons, translating them into the code of 20 amino acids. To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset.
