Modelling the variable severity of Rett syndrome mutations
Rett syndrome is caused by mutations in the MECP2 gene, which encodes a chromosomal protein that binds to methylated DNA. Almost all cases are new mutations that occur in the gametes of parents, as offspring affected by these mutations rarely go on to have children. Males do not survive infancy and hence the overwhelmingly majority of Rett syndrome patients are female. To study its molecular basis, we earlier generated a mouse model of the disorder by deletion of the gene for MeCP2 and found that this closely mirrored the human disorder. More recently, we have developed an allelic series corresponding to the most frequent mutations and here again, the severity spectrum seen in humans is recapitulated in mice. While there are evident differences between humans and mice that can affect the validity of rodent models of human disease, the evidence so far suggests that the function exerted by MeCP2 in the brain, like its amino acid sequence, is almost identical in the two C D organisms. The availability of a convincing model of the human disorder allowed us early on to ask whether Rett syndrome is potentially reversible. The answer, to everyone’s surprise, is “yes”, implying strongly that this condition will be curable in humans too. Soberingly, we reported this observation in 2007, but on its tenth anniversary, there is no treatment so far. There are grounds for optimism, however, as research activity in this area worldwide has never been greater.
Improvements in methods for generating rodent models have meanwhile advanced our understanding of the basic biology of MeCP2, including its role in the brain. It is likely that this knowledge will be required for progress towards rational therapies. One outstanding question concerned whether the characteristic symptoms all originate in the brain, or if so-called “peripheral organs” (everything except the brain and central nervous system) were involved. These concerns were highlighted by early reports that MeCP2 is as highly expressed in some peripheral tissues as it is in the brain. Careful measurement showed firstly that in fact expression in the brain is much higher than elsewhere. More importantly, removal of MeCP2 from all peripheral tissues except the brain gave a mouse that was healthy and showed none of the phenotypic characteristics of the Rett model. Proof that the “seat” of Rett syndrome is indeed the brain makes it clear that therapeutic efforts should be directed at the nervous system.
Ross, P.D. et al. Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes. Hum Mol Genet (2016).
Brown, K. et al. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum Mol Genet 25, 558-70 (2016).
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