title: Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability.
abstract: 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.
authors.affiliation: Molecular Neuropsychiatry & Development Lab, Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Canada.
authors.forename: Muzammil Ahmad
authors.initials: MA
authors.lastname: Khan
authors.forename: Muhammad Arshad
authors.initials: MA
authors.lastname: Rafiq
authors.forename: Abdul
authors.initials: A
authors.lastname: Noor
authors.forename: Shobbir
authors.initials: S
authors.lastname: Hussain
authors.forename: Joana V
authors.initials: JV
authors.lastname: Flores
authors.forename: Verena
authors.initials: V
authors.lastname: Rupp
authors.forename: Akshita K
authors.initials: AK
authors.lastname: Vincent
authors.forename: Roland
authors.initials: R
authors.lastname: Malli
authors.forename: Ghazanfar
authors.initials: G
authors.lastname: Ali
authors.forename: Falak Sher
authors.initials: FS
authors.lastname: Khan
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ayub
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Ibrahim
authors.forename: Michaela
authors.initials: M
authors.lastname: Frye
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ansar
authors.forename: John B
authors.initials: JB
authors.lastname: Vincent
mesh_terms: D044503:5-Methylcytosine; D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D044466:Asian People / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D005260:Female; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008126:Lod Score; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010154:Pakistan; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics* / Q000378:metabolism
chemical_list: D012313:RNA; D044503:5-Methylcytosine; D008780:Methyltransferases; C515610:NSUN2 protein, human