Mystery of Rett Syndrome Lag in Symptom Onset Possibly Explained

For decades, scientists and physicians have puzzled over the fact that infants with the post-natal neuro-developmental disorder Rett syndrome (RTT) show symptoms of the disorder beginning from 6 tp 18 months after birth. In a report published online on April 13, 2015 in PNAS, Dr. Huda Zoghbi and her colleagues from Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, unravel the mystery by looking at when and how the causal gene involved (methyl-CpG binding protein 2 or MeCP2) binds to methylated cytosine over the course of brain development. Using mice in which the MeCP2 protein is tagged with a fluorescent green protein, the scientists determined genome-wide MeCP2 binding profiles in the adult animal brain. In addition to the expected finding of MeCP2 binding to methylated cytosine with guanine (CG) with high affinity, they also found that MeCP2 binds to cytosine when it is followed by either adenine, cytosine, or thymine instead of guanine (non-CG methylation or "mCH" where H is either adenine, cytosine, or thymine). In the PNAS article, the reesearchers said that “unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level ofBdnf, a gene implicated in the pathophysiology of RTT.
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