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March 2001
Vol. 4, No. 3, p 80
diseases and disorders
Luckily, my dear, Rett gave a damn
Chemically, one of the simplest methods for controlling gene expression is DNA methylation. During cell formation, the attachment of a methyl group to a specific nucleotide can direct a cell to become different from those around it, causing it, for example, to become a red blood cell instead of a B cell. But when the machinery of methylation goes awry, all bets are off, and, depending on where and when this occurs, the results can be disastrous. Such is the case with Rett syndrome.

In 1966, Andreas Rett, a pediatric neurologist, described a disorder in young girls with severe psychomotor retardation but who otherwise appear normal. In the first year or so of life, those with the disorder are model infants, calmly and quietly amusing themselves. But as the girls get older (2–4 years), things begin to change. First, the girls develop rhythmic motions such as hand wringing or clasping, and breathing irregularities soon follow. Eventually, the girls become less social—some are described as autistic-like—and speech faculties begin to fail. The girls become tremulous when agitated, which occurs easily, and movement becomes unsteady. When the girls move into the school years, this motor destruction intensifies until most of them are wheelchair-bound. Socially, some girls improve, but many do not.

Rett believed that the disorder was correlated with elevated ammonia levels that he had found in some of his patients, but this correlation did not hold, and the disorder was largely ignored for the next 20 years. In 1983, however, B. Hagberg noticed similar symptoms in girls and coined the name. Further studies have shown Rett syndrome to be one of the most common forms of mental retardation, affecting 1 in 10,000–15,000 girls worldwide.

Because only 1% of Rett syndrome cases are familial, it was difficult to determine its genetics at first. It appeared, however, that Rett syndrome was an X-linked dominant disorder, because it rarely appeared in males, that is, most males with the disease would not survive. By contrast, in girls carrying one mutant copy of the Rett gene, the disorder is not lethal, for there is a 50-50 chance that the mutant X-chromosome will be inactivated in any given cell (a normal process in women). Finally, in 1999, Ruthie Amir and colleagues at the Baylor College of Medicine in Houston and the Stanford University School of Medicine identified the gene responsible for Rett syndrome. The disorder is due to mutations in the gene encoding methyl CpG binding protein 2 (MeCP2).

MeCP2 is an abundant mammalian DNA-binding protein that selectively interacts with 5-methylcytosine residues in the myriad dinucleotide repeats of cytosine–guanosine (CpG) that are typically located at the beginning of a gene. To “turn off” a gene, these so-called CpG islands are transcriptionally silenced by methylation. One domain of MeCP2 binds to the methylcytosine residues, and another domain prevents the expression of the gene. Mutations that lead to Rett syndrome occur in both portions of the MeCP2 protein as well as in the noncoding regions of the gene.

When the gene was discovered, researchers speculated that the disorder might be due to a loss of control of gene expression, such that the wrong proteins were synthesized in cells, causing cellular havoc. Since then, several laboratories have reported physical contact between MeCP2 and proteins involved in chromosome condensation (histone deacetylases), transcriptional repression (the co-repressor Sin3A), and the basal transcriptional machinery. Furthermore, the location of the mutation in MeCP2 is connected to the severity of the disorder, and milder forms of Rett syndrome have been found to occur in boys. Clinical trials are now under way to slow the neurological degeneration associated with this disorder.

Sources: Armstrong, D. D. J. Neuropath. Exp. Neurol. 1997, 56, 843–849; Amir, R. E. Nature Genet. 1999, 23, 185–188; The International Rett Syndrome Association (www.rettsyndrome.org); The Rett Syndrome Research Foundation (www.rsrf.org).

Also, check out the Great Mississippi River Race for Rett Syndrome at www.dreamkeeper.org.

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