191 Investigation of the myxomatous mitral valve prolapse locus on chromosome 16

Myxomatous mitral valve prolapse (MMVP), also called Barlow disease, is a common cardiac disorder characterized by fibromyxomatous changes in the mitral leaflet tissue causing prolapse. Familial studies suggest a genetic heterogeneity and four loci have been identified to date. The MMVP1 locus that we identified in the past in two French families (Disse, Am J Hum Genet 1999) maps on chromosome 16p11-12. The locus interval is relatively large (15 cM). It comprised 185 genes but none has been implicated in the disease, yet. The objective of this work was to test relevant positional candidate genes. Six genes were tested by direct sequencing of all the coding sequences and of the intron-exon boundaries. For each gene, two affected and two unaffected patients of the two families linked to MMVP1 were tested, as well as 46 probands of smaller MVP families. We chose 3 genes belonging to the nodal modulators family that interact with proteins of the TGFβ protein superfamily and known to play a role in heart valve formation and in regulation of collagen and extracellular matrix gene expression. The Nomo1, Nomo2 and Nomo3 genes (located on 16p13.11, 16p12.3 and 16p13.11 respectively) extend on approximately 63 Kb and contain each 30 exons. No pathogenic mutation was identified in the coding region of these genes in these families but only known polymorphisms or rare non-coding variants. We also analysed 3 members of the heparan sulfate sulfotransferase enzymes (HS3ST1, HS3ST2 and HS3ST4) that regulate the heparan sulfate proteoglycan biosynthesis process. The HS3ST2 and HS3ST4 genes are located on 16p12, are extended on approximately123 Kb, but contain each only two exons separated by a large intron. Similarly, the genetic analysis was negative and no pathogenic mutation was identified. This study illustrates the difficulty to identify the causal gene when the linkage interval and the number of genes are large. Priority should be give to fine mapping of the MMVP1 locus.