The NSUN2 gene encodes a methyltransferase with a NOL1/NOP2/Sun domain. NSUN2 catalyzes the methylation of cytosine 34 (C34) of intron-containing tRNA(Leu)(CAA) and of C47 and C48 of tRNA-asp(GTC) precursors. This modification stabilizes anticodon-codon pairing and correctly translates the mRNA. It was also demonstrated that this modification protects tRNA from cleavage and degradation. NSUN2 is known to operate downstream of c-MYC during cell proliferation. Independent of its methyltransferase activity, NSUN2 interacts with the mitotic spindle and plays an important role in cell division.
Four different transcripts of NSUN2 are expressed in human brain at various times during development. And the full length protein is 767 amino acid long.
The NSUN2 gene has 19 exons and spans 34 kb. Mutations in NSUN2 were found to cause autosomal recessive mental retardation 5 (MRT5). Of these mutations are nonsense (p.Q227X, p.Q372X), and missense (p.G679R) ones. In addition to these, a mutation was found to abolish the canonical splice acceptor site of exon 6 in NSUN2 gene, leading to the use of a cryptic splice donor instead. This was found to cause the absence of NSUN2 protein in patient cells.
[See: United Arab Emirates > Martinez et al., 2012].
Komara et al. (2015) studied a 17-year-old Emirati male suffering from intellectual disability. The patient, born to first-degree consanguineous parents, lacked speech and exhibited severe hyperactivity, disruptive and self-harming behavior, a broad gait, mild cerebellar atrophy, severe osteoporosis and facial dysmorphia. Whole exome sequencing helped identify a novel homozygous deletion (c.1020delA) in exon 9 of the patient’s NSUN2 gene. The mutation segregated in an autosomal recessive manner in the family and in-silico analysis by MutationTaster predicted it to be pathogenic. cDNA sequencing and chromatogram analysis found that the mutation resulted in a frameshift, addition of 14 new amino acids and premature termination (G341Vfs*). Expression studies showed a decreased level of NSUN2 mRNA in the patient compared to a healthy control confirming nonsense mediated decay.
Martinez et al. (2012) used exome sequencing to uncover a homozygous mutation in the NSUN2 gene in two Lebanese sibs with developmental delay and dysmorphic features. These sibs were born to consanguineous parents living in the UAE. The novel mutation deletes the splice acceptor site of exon 6 leading to the use of a cryptic splice donor instead. Consequently mRNA instability and lack of NSUN2 protein in patient cells was observed.
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