Molecular characteristics

FN1 gene encodes for the formation of fibronectin which is a glycoprotein of the extracellular matrix. It is essential to the formation of cartilaginous tissues and bones. Mutations in FN1 affect the cysteine residues that form disulfide bonds in the fibronectin type I domain responsible for the three-dimensional structure of the fibronectin. This leads to instability and risk of degradation by metalloproteases 9 and 13.

SMDCF is caused mainly by mutations in the type-I domain. This domain is contained by the N-terminal region which plays a role in initiating fibrils assembly and binding to extra cellular matrix, proteins, and other regions in FN1. Variants in the N-terminal assembly domain lower the number of fibrils in the cell matrix and affect the assembly on the cell. Most mutations substitute the cysteine residues with a hydrophobic amino acid (tyrosine or tryptophan). This substitution disrupts the disulfide bonds in the fibronectin type-I domain. Fibronectin secretion in the extracellular matrix is consequently reduced which could increase the degradation of type I collagen and potentially explain the skeletal changes of patients affected by SMDCF. Another hypothesis is that mineral deposition is affected by FN1 mutations.

SMDCF is inherited in an autosomal dominant manner.