A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy

Abstract

Aims: We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes.Methods: We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected.Results: All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant There is no statistical analysis in this work.

Expression analysis of thg1l during Xenopus laevis development

“…Maternal transcripts of other highly conserved tRNA post-transcriptional modifiers have been reported in Xenopus and zebrafish as, for instance, GTP-binding protein 3 (gtpbp3) (Chen et al, 2016), trna 5-methylaminomethyl-2-thiouridylate methyltransferase (trmu) (zhang et al, 2018), trna nucleotidyl transferase 1 (trnt1) (Deluca et al, 2016) and trna (guanine(37)-n1)-methyltransferase 5 (trmt5) (White et al, 2017). interestingly, in line with data on thg1l, defects in these genes are responsible for rare syndromes characterized by severe pathological traits in humans, such as varying degrees of brain defects, developmental delay, intellectual disability, seizure, dysarthria and ataxia (argente-escrig et al, 2022;Chakraborty et al, 2014;reinhart et al, 1993;sasarman et al, 2015;Wiseman et al, 2013;. successively, thg1l expression levels in Xenopus laevis are quickly reduced, probably due to the consumption of maternal mrna, reaching the lowest expression level by gastrula stage (st. 11), and then remaining almost unchanged until st. 42 tadpole.…”

Research Advances on Deafness Genes Associated with Mitochondrial tRNA-37 Modifications

“… 14 , 17 , 30 Partial pathogenic mutations in the TRMT5 gene have been demonstrated in yeast models, mainly through overexpression in the cDNA of affected individual cells. 22 , 39 , 40 Minxin Guan’s 40 , 41 team successively found that mt-tRNA Asp m.7551A>G mutation caused mitochondrial dysfunction associated with deafness; m.7551A>G mutation produced m 1 G37 modification of mt-tRNA Asp ; and tRNA Ile m.4295A>G associated with deafness introduced TRMT5 -catalyzed m 1 G37 modification. The major defect of this mutation affects the stability and aminoacylation of mutant mt-tRNA Asp and mt-tRNA Ile , resulting in mitochondrial translation impairment, respiratory impairment, decreased membrane potential, reduced ATP production, increased reactive oxygen species production, and pleiotropic effects that promote autophagy.…”