Rett Syndrome

Rett Syndrome is an unusual disorder in girls that manifests itself as an age-dependent progressive decline in cognitive function starting after the first year of life. Among its attributes are diminished brain size, mental retardation, the development of stereotyped hand-wringing movements, and ultimately autism-like features. The gene for Rett Syndrome is on the X chromosome, and embryonic lethality in males (which, of course, have only one copy of the X chromosome) likely leads to the syndrome being selectively observed in girls. However, recent findings of Rett gene mutations in boys may lead to identification of a new homologous syndrome in males.

The Rett gene encodes methyl-CpG binding protein 2 (MECP2, see reference 23). As discussed in the main text, DNA methylation plays a role in transcriptional silencing of genes, and MECP is a protein that binds to methylated DNA sequencing and contributes to suppressing the expression of genes in the vicinity. Thus, loss of MECP2 leads to aberrant expression of genes that are normally silent. There is, of course, the potential that a large number of genes are affected secondarily to loss of MECP2, and experiments are underway to determine target genes of this pathway. Studies in this area are also giving important new insights into the mechanisms involved in DNA methylation-associated transcriptional silencing.

mental retardation syndrome, often abbreviated FRAXA, is one of the most common and debilitating forms of human mental retardation, with a frequency of occurrence in the 1/2,000 range. The FMR1 gene promoter region in normal humans has 5-50 CGG repeats, which do not adversely affect gene expression. Expansion of the repeats into the 200-repeat range leads to loss of gene expression, and the mechanism for this gene loss is complex (see Figure 8). With expanded repeat number, the FMR1 gene promoter region undergoes DNA methylation at C residues of CpG dinu-cleotides, resulting in gene silencing. Of course, loss of gene transcription leads to loss of mRNA and protein synthesis. Again, the means by which DNA methylation leads to transcriptional repression is an active and important area of research (see Box 4). Current models highlight the importance of methyl-CpG binding proteins and their recruitment of histone deacetylation mechanisms as a component of the gene silencing process.

The product of the FMR1 gene is referred to as FMRP, the fragile X mental retardation protein. Although the function of this protein is still being investigated, several studies have indicated that FMRP is an RNA binding protein. As we have already discussed, a current model proposes that FMRP regulates protein synthesis by binding a variety of mRNA species (see Chapters 7 and 8). Moreover, Bill Greenough's group at the University of Illinois has found that FMRP function is necessary for metabotropic glutamate receptor regulation of protein synthesis in synaptoneurosomes, or pinched-off dendritic/presynaptic processes (14). Other studies have also indicated derangements of dendritic spine numbers and morphology in Fragile X tissue samples and in a fragile X mouse

Fragile Dendrite

FIGURE 8 A model for Fragile X Mental Retardation Syndrome. Triplet repeats in the regulatory region, or mutations in the coding region, of the FMR1 gene lead to (among other things) a loss of the FMR1 gene product, FMRP. FMRP is an RNA binding protein proposed to be involved in dendritic mRNA localization and local protein synthesis (see text for additional discussion).

FIGURE 8 A model for Fragile X Mental Retardation Syndrome. Triplet repeats in the regulatory region, or mutations in the coding region, of the FMR1 gene lead to (among other things) a loss of the FMR1 gene product, FMRP. FMRP is an RNA binding protein proposed to be involved in dendritic mRNA localization and local protein synthesis (see text for additional discussion).

model (see also Box 5 and reference 18). Thus, while studies in this area are still at a relatively early stage, the intriguing hypothesis is emerging that FMRP plays a key role in local protein synthesis in dendrites, and, by disrupting this process, leads to the learning derangements of fragile X. As the potential role of FMRP in dendritic protein synthesis was discussed in detail in Chapter 7, I won't reiterate the particulars here. Suffice it to say that once again we see an example of how detailed studies of the molecular mechanisms of synaptic plasticity have converged with studies of a human learning disorder.

B. Fragile X Mental Retardation Type 2

Fragile X mental retardation type 2 (FMR2), similar to the case with FMR1, results from expansion and methylation of a CCG trinucleotide repeat located in exon

1 of the X-linked FMR2 gene, which results in transcriptional silencing. While the FMR1 syndrome and FMR2 mental retardation share a similar name and mechanism of mutation, FMR2 (a.k.a. FRAXE) is "nonsyndromic" (see Box 6). Also, in contrast to the profound mental retardation of FMR1, loss of the FMR2 gene product is associated with a milder mental impairment. Among those with the FMR2 pheno-type, delays in language development are particularly prominent, and some FMR2 patients also have behavioral deficits, such as attention deficit, hyperactivity, and autistic-like behavior. Also in contrast to Fragile X type 1, which is likely the most common form of mental retardation, expansion of the FMR2-associated CCG repeat is quite rare, with an incidence estimated at less than 1:50,000.

Expansion and methylation of a CCG repeat in the 5' untranslated region (UTR)

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