The gene for microfibril-associated protein-1 (MFAP1) is located several megabases centromeric to FBN1 and is not mutated in Marfan syndrome

Linkage studies have mapped the Marfan syndrome (MFS) locus to chromosome region 15q15-q21 with no convincing evidence of genetic heterogeneity. The fibrillin-1 (FBN1) gene, located at 15q21.1, that encodes the major component of the defective microfibrils, has been identified as the gene for MFS. However, extensive mutation screening in many laboratories has detected FBN1 mutations in only a fraction of MFS probands studied, leading to the hypothesis that the missing mutations could involve another microfibril gene located in the same region. Recently, the gene for microfibril-associated protein-1 (MFAP1, also called AMP) has been isolated and mapped to the 15q15-q21 region that overlaps the location of the FBN1 gene. Here we report that the two loci are physically close, making MFAP1 an alternative positional candidate gene for MFS. We have carried out MFAP1 mutation screening and gene expression analysis in 48 probands with MFS or related phenotypes who were selected for this study because their fibroblast cultures synthesized fibrillin at normal levels. No MFAP1 mutations were identified, and transcription occurred equally from both alleles. We conclude that the MFAP1 locus is not a reservoir for the hidden MFS mutations.