1
Mutations in NSUN2 Cause Autosomal- Recessive Intellectual Disability.
Am J Hum Genet. 2012 May 4; 90(5):847-55
All selected articles haveThis article has been added to your saved articles
You can follow/unfollow articles via MyF1000 or via the article or browse pages.
06 Jun 2012
Confirmation
DOI: 10.3410/f.716297851.791652839
Mutations leading to loss of expression of the NSUN2 gene, which stabilises anticodon-codon pairing by methylating the wobble codon of tRNA(Leu)(CAA), were shown to be responsible for impairment of higher cognitive function in three consanguineous families. A related paper confirms this finding in an...Continue reading
Mutations leading to loss of expression of the NSUN2 gene, which stabilises anticodon-codon pairing by methylating the wobble codon of tRNA(Leu)(CAA), were shown to be responsible for impairment of higher cognitive function in three consanguineous families. A related paper confirms this finding in an additional family {1}. The approach was traditional homozygosity mapping and sequencing, emphasising yet again the power of this approach and the importance of identifying and characterising suitable families. This is particularly important for conditions as general as intellectual disability, which is as prevalent as affecting 1% to 3% of the population but caused by a very large number of different genes. The gene is expressed in the normal fetal brain, and absence of this transcript in affected individuals could affect gene transcription and/or translational regulation. A Drosophila melanogaster deletion model demonstrated that, although this gene was not crucial to survival, gross nervous system function or elementary behaviour (e.g. locomotion), it was impaired in learning behaviour. Although the Drosophila model added to the case that these are causative mutations, the genetic evidence on its own is compelling. This is the third RNA methyltransferase to be associated with intellectual impairment.
References
1.
Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability.
American journal of human genetics 2012 May 4; 90(5): 856-63
PMID: 22541562
DOI: 10.1016/j.ajhg.2012.03.023
Disclosures
None declared
Add Comment
Malcolm S and Abu-Amero S: F1000Prime Recommendation of [Abbasi-Moheb L et al., Am J Hum Genet 2012, 90(5):847-55]. In F1000Prime, 06 Jun 2012; DOI: 10.3410/f.716297851.791652839. F1000Prime.com/716297851#eval791652839
F1000Prime Recommendations, Dissents and Comments for [Abbasi-Moheb L et al., Am J Hum Genet 2012, 90(5):847-55]. In F1000Prime, 23 May 2013; F1000Prime.com/716297851
Only registered/signed-in users can make comments.
Sign in or Subscribe to create your user account and join the discussion.
Sign in or Subscribe to create your user account and join the discussion.
No comments yet.
With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(∗)] and c.1114C>T [p.Gln372(∗)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(∗)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development.
Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2012.03.021
PMID: 22541559
