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  Mutations in NSUN2 cause autosomal-recessive intellectual disability

Abbasi-Moheb, L., Mertel, S., Gonsior, M., Nouri-Vahid, L., Kahrizi, K., Cirak, S., et al. (2012). Mutations in NSUN2 cause autosomal-recessive intellectual disability. American Journal of Human Genetics, 90(5), 847-855. doi:10.1016/j.ajhg.2012.03.021.

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© 2012 The American Society of Human Genetics




Abbasi-Moheb, Lia1, 2, Author              
Mertel, Sara3, Author
Gonsior, Melanie3, Author
Nouri-Vahid, Leyla2, Author
Kahrizi, Kimia2, Author
Cirak, Sebahattin4, Author
Wieczorek, Dagmar5, Author
Motazacker, M. Mahdi6, Author              
Esmaeeli-Nieh, Sahar6, Author              
Cremer, Kirsten5, Author
Weissmann, Robert7, Author
Tzschach, Andreas6, Author              
Garshasbi, Masoud6, Author              
Abedini, Seyedeh S.2, Author
Najmabadi, Hossein2, Author
Ropers, Hans-Hilger6, Author              
Sigrist, Stephan J.3, 8, Author
Kuss, Andreas W.1, Author              
1Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, 14195 Berlin, Germany, ou_1479644              
2Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran 1985713834, Iran, ou_persistent22              
3Institute for Biology/Genetics, Freie Universität Berlin, 14195 Berlin, Germany, ou_persistent22              
4Great Ormond Street Children's Hospital, Institute of Child Health, 30 Guilford Street, London WC1N1EH, UK, ou_persistent22              
5Institut für Humangenetik, Universitätsklinikum, 45147 Essen, Germany, ou_persistent22              
6Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, 14195 Berlin, Germany, ou_1433549              
7Institute for Human Genetics, University Medicine Greifswald & Interfaculty Institute for Genetics and Functional Genomics, Ernst Moritz Arndt University, Greifswald, 14195 Berlin, Germany, ou_persistent22              
8NeuroCure Cluster of Excellence, Charité, 10117 Berlin, Germany, ou_persistent22              


Free keywords: Adolescent Adult Animals Child Cloning, Molecular *Codon, Nonsense Consanguinity Drosophila/genetics Exons Female *Genes, Recessive Genetic Linkage Genotype Homozygote Humans Intellectual Disability/*genetics/physiopathology Male Methyltransferases/*genetics/metabolism Middle Aged Pedigree Phenotype Young Adult
 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.


Language(s): eng - English
 Dates: 2012-04-262012-05-04
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2012.03.021
 Degree: -



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Title: American Journal of Human Genetics
Source Genre: Journal
Publ. Info: American Society of Human Genetics
Pages: - Volume / Issue: 90 (5) Sequence Number: - Start / End Page: 847 - 855 Identifier: ISSN: 0002-9297
CoNE: https://pure.mpg.de/cone/journals/resource/954925377893