and 16. Normally these satellites are heavily methylated, but in ICF syndrome they are almost completely unmethylated in all tissues.92 Most affected patients succumb to infectious disease before adulthood.
Rett syndrome is a postnatal neurodevelopmental disorder that occurs almost exclusively in girls.92-94 It is one of the commonest forms of intellectual disability in young girls and it is characterized by a period of early normal growth and development followed by regression, loss of speech and acquired motor skills, stereotypical hand movements, and seizures. In sporadic cases, affected girls are normal at birth and achieve expected developmental milestones until
6_18 months of age when brain growth slows and growth failure occurs. This disorder is associated with both nonsense and missense mutations of the X-linked gene encoding the methyl-CpG-binding protein, MECP2.
The identification of the genetic cause of Rett syndrome was a major advance in clinical neurology and epigenetics.95,96 Up to 96% of classic Rett syndrome cases are accounted for by MECP2 mutations. Nearly 70% of the mutations arise from C-T transitions at eight CpG dinucleotides, whereas carboxy-terminal deletions occur in 10_15% of patients. Female patients with phenotypes distinct from the classic presentation of Rett syndrome have also been identified. Males with MECP2 mutations fall into three groups, those with Rett syndrome, those with severe encephalopathy and infantile death, and those with severe neurological and/or psychiatric symptomatology.
Recently, Terumi Kohwi-Shigematsu and colleagues have shown loss of silent-chromatin looping and impaired imprinting of DLX5 in mice.97 Using a modified ChIP-based cloning strategy to search for Mecp2 target genes in mouse brain, they identified DLX5, a maternally expressed gene on mouse chromosome 6, as a direct target of Mecp2. The importance of DLX5 lies in the production of g-aminobutyric acid (GABA). In the Mecp2 null-mouse model, they showed that repressive histone modification at Lys-9 and the formation of a higher order chromatin loop structure were mediated by Mecp2 and specifically associated with silent chromatin at Dx15-Dx16. Because loss of imprinting of DLX5 may alter GABAergic neuron activity, this finding suggests that dysregulation of DLX5 by mutation of MeCP2 might contribute to some of the phenotypes of this syn-drome.97 Current data, as described by Moretti and Zoghbi,95 suggest that several putative genes are targeted by MECP2, and that the elucidation of mechanisms that give rise to the characteristic features of Rett syndrome is a key challenge for the future.
Was this article helpful?