A GLY1127SER MUTATION IN AN EGF-LIKE DOMAIN OF THE FIBRILLIN-1 GENE IS A RISK FACTOR FOR ASCENDING AORTIC-ANEURYSM AND DISSECTION

Ascending aortic disease, ranging from mild aortic root enlargement to aneurysm and/or dissection, has been identified in 10 individuals of a kindred, none of whom had classical Marfan syndrome (MFS). Single-st rand conformation analysis of the entire fibrillin-1 (FBN1) cDNA of an affected family member revealed a G-to-A transition at nucleotide 337 9, predicting a Gly1127Ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. Th is mutation was present in 9 of 10 affected family members and in 1 yo ung unaffected member but was not found in other unaffected members, i n 168 chromosomes from normal controls, and in 188 chromosomes from ot her individuals with MFS or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a s ignificant role in modulating the phenotype in this family. Pulse-chas e studies revealed normal fibrillin synthesis but reduced fibrillin de position into the extracellular matrix in cultured fibroblasts from a Gly1127Ser carrier. We postulate that the Gly1127Ser FBN1 mutation is responsible for reduced matrix deposition. We suggest that mutations s uch as this one may disrupt EGF-like domain folding less drastically t han do substitutions of cysteine or of other amino acids important for calcium-binding that cause classical MFS. The Gly1127Ser mutation, th erefore, produces a mild form of autosomal dominantly inherited weakne ss of elastic tissue, which predisposes to ascending aortic aneurysm a nd dissection later in life.