Phenotypic and molecular heterogeneity in fibrodysplasia ossificans progressiva

Fibrodysplasia (myositis) ossificans progressiva (FOP) is an extremely rare inherited disorder in which progressive ossification of major striated mus cles, often following injury, is associated with abnormal skeletal patterni ng. Altered expression of bone morphogenetic proteins may be a contributory cause. To examine this hypothesis, we compared the patterns of expression of bone morphogenetic proteins (BMPs) mRNAs from lymphoblastoid cell lines from two small multigenerational families with autosomal dominant transmiss ion of FOP. Although affected members of both families showed the character istic phenotype of FOP, one family was more severely affected than the othe r. Expression of mRNAs for BMP-1, 2, 3, 5, and 6 mRNAs were not detected wi thin the more severely affected family, but BMP-4 mRNA was expressed in aff ected but not unaffected members of this family. The results of linkage exc lusion analysis using a highly polymorphic microsatellite marker near the B MP-4 gene were consistent with linkage of FOP and BMP-4 in this family. Wit hin the less severely affected family, affected and unaffected members show ed similar levels of mRNA expression of BMPs 1, 2, 4, and 5, and linkage of FOP to the BMP-4 gene was excluded. it is concluded that clinical, radiogr aphic, and biochemical data in these two families with FOP establish clinic al and molecular heterogeneity and also suggest the possibility of genetic heterogeneity.