Khan, Muzammil A. and Rafiq, Muhammad A. and Noor, Abdul and Hussain, Shobbir and Flores, Joana V. and Rupp, Verena and Vincent, Akshita K. and Malli, Roland and Ghazanfar, Ali and Khan, Falak S. and Ishak, Gisele E and Doherty, Dan and Weksberg, Rosanna and Muhammad, Ayub and Windpassinger, Christian and Ibrahim, Shahnaz and Frye, Michaela and Muhammad, Ansar and Vincent, John B. (2012) 'Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability.', American journal of human genetics., 90 (5). pp. 856-863.
Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32–p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development.
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|Publisher Web site:||http://dx.doi.org/10.1016/j.ajhg.2012.03.023|
|Publisher statement:||NOTICE: this is the author’s version of a work that was accepted for publication in American journal of human genetics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in American journal of human genetics, 90, 5, 2012, 10.1016/j.ajhg.2012.03.023|
|Record Created:||07 Sep 2012 16:20|
|Last Modified:||09 Oct 2012 12:47|
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