EXTRA CYSTEINE IN ONE OF THE NON-CALCIUM-BINDING EPIDERMAL GROWTH FACTOR-LIKE MOTIFS OF THE FBN1 POLYPEPTIDE IS CONNECTED TO A NOVEL VARIANT OF MARFAN-SYNDROME

We present here a family with a clinical phenotype resembling Marfan s yndrome (MFS), and displaying joint contracture and episodes of knee j oint effusions, but lacking the cardiovascular features of the syndrom e. The phenotype of this family represents a unique mixture of connect ive tissue symptoms, some of which are found in classical MFS and some of which are typical of dominant ectopia lentis. Linkage analyses sug gested a linkage (LOD score 2.4; theta = 0) between the phenotype of t he family and a polymorphic marker in the vicinity of the fibrillin lo cus on chromosome 15 (FBN1). Furthermore, a novel transition mutation was identified in the FBN1 gene in all the affected members of the fam ily. In contrast to the majority of fibrillin mutations reported so fa r, this mutation substitutes a cysteine for arginine, producing an ext ra cysteine in one of the non-calcium-binding EGF-like moths of the fi brillin polypeptide, most probably disturbing the formation of one of the three disulfide bridges known to be essential for the normal confo rmation of this motif.