Résumé :
|
Communication n° 508 Introduction : Congenital muscular dystrophy type 1A (MDC1A) is the most frequent form of CMD in the European population, accounting for 30-50% of the cases. Clinical symptoms include hypotonia, elevated CK, no independent ambulation, respiratory insufficiency and cerebral white matter abnormalities. The LAMA2 gene (MIM#156225) that encodes the ?2 chain of laminin, is implicated in this disease. Mutations described to date are mostly of the nonsense or deletion/duplication type, resulting in premature polypeptide termination, thereby explaining the frequently observed total absence of laminin ?2 in muscle fibers of these patients. Objectives : i) LAMA2 mutation screening in a subset of Portuguese patients with CMD and absence of laminin ?2 staining in muscle biopsy. ii) Detection of new informative intragenic SNPs that could be potentially useful both in haplotyping and in the detection of large heterozygous deletions. Methods : A total of 10 patients and their relatives were included in this study. All 65 LAMA2 exons were screened by direct sequencing. Linkage analysis was performed in some families, using STRs surrounding the LAMA2 locus (D6S1715, D6S407, D6S1620, D6S1705, D6S1572). Molecular changes at the RNA level were studied by RT-PCR and sequencing. Results : Causative mutations were identified in all patients studied. These included nonsense, frameshift and splice mutations that could account for the clinical phenotype. Nine different mutations were detected, 5 of which have not been reported previously (c.4739dupG, c.7489_7492dupAAAG, c.363C>A, c.8244+1G>A, c.4318C>T). Twenty-six SNPs were found in the course of the study. Conclusions : The detection rate was high, with mutations scattered throughout the gene. Given the wide spectrum and lack of mutation hotspots, systematic screening of the entire gene should be carried out in patients with clinical signs of MDC1A and compatible biopsy. Besides carrier detection, this work enables accurate prenatal testing, which hitherto has depended on haplotyping and immunocytochemical analysis on chorionic villi.
|