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Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability

Khan, M.A.; Rafiq, M.A.; Noor, A.; Hussain, S.; Flores, J.V.; Rupp, V.; Vincent, A.K.; Malli, R.; Ali, G.; Khan, F.S.; Ishak;, G.E.; Doherty, D.; Weksberg, R.; Ayub, M.; Windpassinger, C.; Ibrahim, S.; Frye, M.; Ansar, M.; Vincent, J.B.

Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability Thumbnail


M.A. Khan

M.A. Rafiq

A. Noor

S. Hussain

J.V. Flores

V. Rupp

A.K. Vincent

R. Malli

G. Ali

F.S. Khan

G.E. Ishak;

D. Doherty

R. Weksberg

M. Ayub

C. Windpassinger

S. Ibrahim

M. Frye

M. Ansar

J.B. Vincent


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.


Khan, M., Rafiq, M., Noor, A., Hussain, S., Flores, J., Rupp, V., …Vincent, J. (2012). Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability. American Journal of Human Genetics, 90(5), 856-863.

Journal Article Type Article
Publication Date May 1, 2012
Deposit Date Sep 6, 2012
Publicly Available Date Oct 9, 2012
Journal American Journal of Human Genetics
Print ISSN 0002-9297
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 90
Issue 5
Pages 856-863


Accepted Journal Article (287 Kb)

Copyright 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

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