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NSun2 – mechanistic explanation for human phenotype

Several genetic mutations in the NSUN2 gene have been identified to cause a syndromic form of intellectual disability and a Dubowitz-like syndrome in humans. The NSUN2 gene carries a homozygous mutation that leads to the loss of the NSun2 protein. Besides intellectual disability, the patients show further symptoms of neurological abnormalities such as microcephaly, behavioural deficits, speech delay, abnormal gait as well as morphological features including growth retardation, facial and cutaneous abnormalities. While some of the morphological symptoms are also present in loss-of-function transgenic mouse models for NSun2, neurological defects have not been studied yet.

The Nsun2 gene is coding for a cytosine-5 RNA methyltransferase. The loss of this enzyme leads to an increase of the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5’ tRNA-derived small RNA fragments. The accumulation of tRNA fragments activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Since these neurons are of importance for intellectual abilities the knowledge about the molecular processes helps to understand the human phenotype. Methylation of the tRNAs protects the molecules against angiogenin mediated cleavage.

The analysis of NSun2-deficient mice in the German Mouse Clinic aimed to answer the question if these processes lead to a detectable phenotype in the mouse that allows conclusions about neuronal or cognitive deficits as observed in humans. In the behavior screen of the German Mouse Clinic in the NSun2-deficient mice hyperactivity was observed in the open field and changes on the Rotarod. These results lead to the conclusion that the function of NSun2 is relevant for the behavior in the mouse.

Furthermore the screeners found that the loss of NSun2 leads to cognitive deficits in male mice and to a reduction of the rate of neurogenesis which correlates with cognitive abilities.

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders; Blanco et al., The EMBO Journal (2014) 33: 2020–2039, DOI 10.15252/embj.201489282