Session 3: Molecular Genetics of Autism
Ignatia B. Van den Veyver, MD
Rett syndrome is a primarily sporadic neurodevelopmental disorder and a leading cause of mental retardation in females, with an incidence of 1/10,000-1/15,000. Affected girls usually have apparently normal development until 6 - 18 months of age, at which stage they start to regress. They have a deceleration of head growth, loose acquired hand skills and speech, develop stereotyped hand movements (clapping, washing, wringing), seizures, breathing irregularities, autonomic dysfunction and gait ataxia and apraxia. They also develop autistic behavior including deterioration of eye contact, and loss of communication skills and social interaction.
Based on the fact that primarily females are affected and on inheritance through maternal lineages in the few familial cases, it was proposed that RTT is an X-linked dominant disorder. After exclusion mapping and candidate gene analysis, we identified mutations in the MECP2 gene in sporadic and familial cases of Rett syndrome. This gene encodes methyl CpG-binding protein 2, a protein that binds 5-methylcytosine in CpG dinucleotides in the genome via its methyl CpG-binding domain (MBD).This leads to the recruitment, via the transcriptional repression domain (TRD), of a repressor complex containing HDAC1 and 2 and the co-repressor Sin3A, resulting in deacetylation of core histones, compaction of chromatin and transcriptional repression of downstream genes.
Mutations have now been identified in about 80% of classic Rett syndrome patients. Truncating and missense mutations have been found throughout the gene, suggesting that a total or partial loss of function is responsible for the phenotype. Missense mutations tend to cluster towards the N-terminus, while truncating mutations are more distal. C to T transitions at 8 CpG dinucleotides hotspots account for 65% of all mutations (over 80% of all point mutations), while 11% are multinucleotide deletions in the C-terminal portion of the coding region. No clear correlation can be found between genotype and phenotypic features of classic and variant Rett syndrome. X chromosome inactivation patterns (XCI) appear to affect severity of the symptoms. Affected girls have mostly random XCI, while unaffected or mildly symptomatic obligate carriers in familial cases have skewed patterns, presumably in favor of the wild-type X.
Because of the presence of mental retardation in Rett syndrome, a few studies on populations with non-specific mental retardation have yielded mutations in both sporadic and familial female and male cases. Those mutations are typically predicted to have a milder effect (especially in males), or are associated with non-random XCI in females.
A few laboratories have now also investigated the incidence of MECP2 mutations in the autistic population. Mutations have been reported in 0-4% of patient studied thus far. A small percentage of patients originally diagnosed as Angelman syndrome (AS), another condition with some autistic characteristics, were found to have MECP2 mutations. More than half of these could be reclassified as Rett syndrome patients on reexamination. The current available data indicate that MECP2 mutations may be responsible for a small percentage of autism cases. Moreover, once identified, some of its downstream target genes, whose expression might be altered because of loss of function of MeCP2 may become good candidates. Current studies are focusing on the identification of the downstream targets of MeCP2 in animal models with Rett syndrome-causing mutations or in cell lines of human patients using such approaches as cDNA microarray hybridization.
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