title: Mutations in NSUN2 cause autosomal-recessive intellectual disability.
abstract: 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.
authors.affiliation: Max Planck Institute for Molecular Genetics, Ihnestraße 73, Berlin, Germany.
authors.forename: Lia
authors.initials: L
authors.lastname: Abbasi-Moheb
authors.forename: Sara
authors.initials: S
authors.lastname: Mertel
authors.forename: Melanie
authors.initials: M
authors.lastname: Gonsior
authors.forename: Leyla
authors.initials: L
authors.lastname: Nouri-Vahid
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: M Mahdi
authors.initials: MM
authors.lastname: Motazacker
authors.forename: Sahar
authors.initials: S
authors.lastname: Esmaeeli-Nieh
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.forename: Robert
authors.initials: R
authors.lastname: Weißmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
authors.forename: Seyedeh S
authors.initials: SS
authors.lastname: Abedini
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.forename: H Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sigrist
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Kuss
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D003001:Cloning, Molecular; D018389:Codon, Nonsense; D003241:Consanguinity; D004330:Drosophila / Q000235:genetics; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D018389:Codon, Nonsense; D008780:Methyltransferases; C515610:NSUN2 protein, human