Mutations in NSUN2 Cause Autosomal-Recessive Intellectual Disability

Max Planck Institute for Molecular Genetics, Ihnestraße 73, Berlin, Germany.
The American Journal of Human Genetics (Impact Factor: 10.93). 04/2012; 90(5):847-55. DOI: 10.1016/j.ajhg.2012.03.021
Source: PubMed


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.

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Available from: Sebahattin Cirak,
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    • "While the disease-associated genetic variants are characterized by Mendelian inheritance, these findings suggest that altered RNA methylation patterns can have a considerable pathophysiological relevance. Indeed, mutations in another RNA modification enzyme, the NSUN2 methyltransferase, have been shown to cause autosomal recessive intellectual disability [63], [64]. A diagnostic tRNA substrate of NSUN2 appeared clearly hypomethylated in dermal fibroblasts from mutation carriers [65], thus suggesting that RNA hypomethylation is involved in the molecular disease pathology. "
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    ABSTRACT: Genomic concepts are based on the assumption that phenotypes arise from the expression of genetic variants. However, the presence of non-Mendelian inheritance patterns provides a direct challenge to this view and suggests an important role for alternative mechanisms of gene regulation and inheritance. Over the past few years, a highly complex and diverse network of noncoding RNAs has been discovered. Research in animal models has shown that RNAs can be inherited and that RNA methyltransferases can be important for the transmission and expression of modified phenotypes in the next generation. We discuss possible mechanisms of RNA-mediated inheritance and the role of these mechanisms for human health and disease.
    PLoS Genetics 04/2014; 10(4):e1004296. DOI:10.1371/journal.pgen.1004296 · 7.53 Impact Factor
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    • "Although the physiological roles of ID genes are heterogeneous, increasing numbers of methyltransferases are being implicated in ID, stressing the essential role that methylation plays in the development and function of the central nervous system. For instance, ID has been linked to mutations in the methyltransferases NSUN2 (4,5) EHMT1 (6), FTSJ1, (7) and TRMT1 (8), which have diverse molecular substrates. Here, we report the identification of methyltransferase-like 23 gene (METTL23) truncating mutations in two nonsyndromic ID families, one Austrian and the other Pakistani family, and discuss potential substrates for this protein. "
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    ABSTRACT: We describe the characterization of a gene for mild nonsyndromic autosomal recessive intellectual disability (ID) in two unrelated families, one from Austria, the other from Pakistan. Genome-wide single nucleotide polymorphism microarray analysis enabled us to define a region of homozygosity by descent on chromosome 17q25. Whole-exome sequencing and analysis of this region in an affected individual from the Austrian family identified a 5 bp frameshifting deletion in the METTL23 gene. By means of Sanger sequencing of METTL23, a nonsense mutation was detected in a consanguineous ID family from Pakistan for which homozygosity-by-descent mapping had identified a region on 17q25. Both changes lead to truncation of the putative METTL23 protein, which disrupts the predicted catalytic domain and alters the cellular localization. 3D-modelling of the protein indicates that METTL23 is strongly predicted to function as an S-adenosyl-methionine (SAM)-dependent methyltransferase. Expression analysis of METTL23 indicated a strong association with heat shock proteins, which suggests that these may act as a putative substrate for methylation by METTL23. A number of methyltransferases have been described recently in association with ID. Disruption of METTL23 presented here supports the importance of methylation processes for intact neuronal function and brain development.
    Human Molecular Genetics 03/2014; 23(15). DOI:10.1093/hmg/ddu115 · 6.39 Impact Factor
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    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.
    The American Journal of Human Genetics 04/2012; 90(5):856-63. DOI:10.1016/j.ajhg.2012.03.023 · 10.93 Impact Factor
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