New mechanism for learning disability in Down's syndrome

30 May 2013

Researchers have reported a novel molecular mechanism through which triplication of chromosome 21 could cause deficits in learning and memory in Down’s syndrome patients.

Down’s syndrome is caused by the abnormal inheritance of three (rather than the usual two) copies of chromosome 21.  At a genetic level this leads to higher than normal levels of expression of the many genes and non-coding RNAs that are encoded on this chromosome.  Clinically this results in a complex constellation of symptoms of which the most prominent is a varying degree of learning disability.  Learning disability in Down’s syndrome is associated with reductions in the number and activity of the synapses (connections) made between neurons in the brain, and so understanding the mechanisms underlying these neurodevelopmental abnormalities may provide the key to ameliorating the effects of this disorder.
 
A new study in Nature Medicine reports that the protein encoded by the sorting nexin 27 (SNX27) gene, which is present at abnormally low levels in the brain of Down’s syndrome patients, may underlie the presence of learning disabilities in this condition. 
 
The researchers showed, by knocking out the Snx27 gene in mice, that its expression is vital for brain development.  In particular they discovered that Snx27 is vital for the maintenance of synaptic activity and consequently for learning and memory, deficits in which underlie learning disability in Down’s syndrome patients.  In a key experiment that linked these observations in mice more directly with the symptoms of Down’s syndrome in humans, the team were able to demonstrate that increasing Snx27 levels in a mouse model of Down’s syndrome could reverse the learning and memory deficits from which it is suffers. 
 
In an interesting genetic twist, the dysregulation of SNX27 in Down’s syndrome is the not the direct result of the overexpression of a gene on Chromosome 21, but is instead the indirect result of the overexpression of a microRNA (miR-155) encoded on that chromosome, which in turn regulates the expression of a transcription factor (c/EBPbeta) that controls the expression of SNX27.  This convoluted pathway from genomic abnormality (triplication of a microRNA) to phenotypic effect highlights the one of the challenges researchers and clinicians face in interpreting and predicting the clinical consequences of genomic variation.
 
This research suggests that the low levels of SNX27 observed in the brains of Down’s syndrome patients may contribute to their learning disability and that the neuronal processes in which SNX27 is involved may be targets for therapies to improve their cognition. Such conclusions must, however, be treated with great caution as over 500 genes are triplicated in Down’s syndrome and the single microRNA investigated in this study alone has the ability to influence the expression of a further 140 genes.  This level of genetic complexity will require the application of systems biology-type approaches to disentangle the way in which the products of these many genes interact and to identify which, if any, individual genes or pathways predominate in the development of learning disability and other clinical features of Down’s syndrome.

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