Eur J Med Genet. 2006 Jan-Feb;49(1):9-18.
Spectrum and distribution of MECP2 mutations in 424 Rett syndrome patients: a molecular update
Philippe C, Villard L, De Roux N, Raynaud M, Bonnefond JP, Pasquier L, Lesca G, Mancini J, Jonveaux P, Moncla A, Chelly J, Bienvenu T.
Abstract
Mutations in the MECP2 (Methyl-CpG-binding protein) gene have been reported to cause Rett syndrome (RTT), an X-linked progressive encephalopathy. Recent studies have identified large gene rearrangements that escape the common PCR-based mutation screening strategy and mutations in a novel MeCP2 isoform (named MECP2B). We have collected the results of MECP2 mutational analysis concerning 424 RTT patients conducted in eight laboratories in France. In total, 121 different MECP2 mutations were identified. R168X (11.5%) is the most common of MECP2 mutations, followed by R270X (9%), R255X (8.7%), T158 M (8.3%) and R306C (6.8%). Only eight mutations had relative frequency>3%. Large and complex rearrangements not previously detected using only a PCR-based strategy represent 5.8% of MECP2 mutations. On the contrary, mutation in exon 1 appears to be rare (less than 0.5%). These data demonstrate the high allelic heterogeneity of RTT in France and suggest that routine mutation screening in MECP2 should include quantitative analysis of the MECP2 gene. This study represents an important instrument for molecular diagnosis strategy and genetic counseling in RTT families.
Lay Summary
As we know, the majority of MeCP2 mutations are identified by directly reading the DNA sequence of the gene in patient samples, and looking for DNA sequences different from the norm. However, we now know that there exists a significant number of Rett patients where no MeCP2 mutation has been found via direct DNA sequence reading. Rather, large deletions of the MeCP2 gene, or rearrangements of the MeCP2 gene, are found in these cases. In this study, MeCP2 mutations in 424 French Rett patients were characterized. In total, 121 different MeCP2 mutations were found, existing in occurrences similarly found in other international studies. Interestingly, close to 6% of the patients possessed mutations of the deletion/rearrangement type. Additionally, it was further shown that mutations unique to the relatively newly discovered form of MeCP2 were rare. In summary, this report echoes the take-home-point of a study we highlighted late last year (Archer et al., Gross rearrangements of the MeCP2 gene are found in both classical and atypical Rett Syndrome.), again reinforcing the belief that screening for MeCP2 mutations by DNA sequencing alone is not enough, and that analysis of the whole gene structure is important in diagnostic assessments.