Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling 
genetic disorder characterized by congenital malformation of the great toes and 
by progressive heterotopic endochondral ossification in predictable anatomical 
patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur 
in lymphoblastoid cells and in lesional cells of patients with FOP, mutations 
have not been identified in the BMP4 gene, suggesting that the mutation in FOP 
may reside in a BMP4-interacting factor or in another component of the BMP4 
pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A 
recent case report described a heterozygous 42-bp deletion in the protein-coding 
region of the noggin gene in a patient with FOP. In order to determine if noggin 
mutations are a widespread finding in FOP, we examined 31 families with 1 or 
more FOP patients. Linkage analysis with an array of highly polymorphic 
microsatellite markers closely linked to the noggin gene was performed in four 
classically-affected multigenerational FOP families and excluded linkage of the 
noggin locus to FOP (the multipoint lod score was -2 or less throughout the 
entire range of markers). We sequenced the noggin gene in affected members of 
all four families, as well as in 18 patients with sporadic FOP, and failed to 
detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 
4 of these patients plus an additional 9 patients also failed to reveal any 
mutations. Among the samples analyzed by SSCP and DNA sequencing was an 
independently obtained DNA sample from the identical FOP patient previously 
described with the 42-bp noggin deletion; no mutation was detected. Examination 
of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate 
the possibility of a somatic mutation in the noggin gene which could be carried 
by a small subset of white blood cells, also failed to detect the presence of 
the reported 42-bp deletion. We conclude that mutations in the coding region of 
noggin are not associated with FOP.