A NOVEL DE-NOVO MUTATION IN EXON-14 OF THE FIBRILLIN-1 GENE ASSOCIATED WITH DELAYED SECRETION OF FIBRILLIN IN A PATIENT WITH A MILD MARFAN PHENOTYPE

The Marfan syndrome, an autosomal dominant heritable disorder of conne ctive tissue, is caused by mutations in the gene for fibrillin-1, FBN1 . A novel FBN1 mutation was identified using temperature-gradient gel electrophoresis of a reverse-transcribed polymerase chain reaction pro duct spanning exons 14 to 16. The mutation, G1760A, is predicted to re sult in the amino acid substitution C587Y and thus to disrupt one of t he disulfide bonds of the calcium-binding epidermal growth factor-like module encoded by exon 14. C587Y was found to be a de novo mutation i n a relatively mildly affected 15-year-old girl whose clinical phenoty pe was characterized mainly by ectopia lentis and thoracic scoliosis. Metabolic labeling of cultured dermal fibroblasts from the affected pa tient demonstrated delayed secretion of fibrillin with normal synthesi s and no decrease in incorporation into the extracellular matrix compa rtment. Fibrillin immunostaining of confluent dermal fibroblast cultur es revealed no visible difference between the patient's cells and cont rol cells. Characterization of many different FBN1 mutations from diff erent regions of the gene may provide a better understanding of clinic al and biochemical genotype-phenotype relationships.