I. Schrijver et al., Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: Distinct effects on biochemical and clinical phenotypes, AM J HU GEN, 65(4), 1999, pp. 1007-1020
Citations number
50
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
Fibrillin-1 (FBN1) contains 47 epidermal growth factor (EGF)-like domains c
haracterized by six conserved cysteine residues. Cysteine substitutions tha
t disrupt one of the three disulfide bonds are frequent causes of Marfan sy
ndrome (MFS). We identified 19 new substitutions involving cysteine residue
s in each of the six positions of EGF-like domains. Allele-specific mRNA as
says revealed equal abundance of mutant and normal FBN1 transcripts in all
10 individuals studied. Quantitative pulse-chase analysis of fibrillin prot
ein was performed on 25 mutant fibroblast strains with substitutions of 22
different cysteine residues in 18 different EGF-like domains spanning the e
ntire gene. Normal synthesis and stability of mutant fibrillin molecules wa
s seen in 20/25 individuals, 11 of whom showed delayed intracellular proces
sing and/or secretion. In the remaining five cases, the mutant protein was
apparently unstable. In four of these five cases, the second or third disul
fide bond of EGF-like domains immediately preceding an 8-cysteine or hybrid
domain was affected. All but two mutations caused severe reduction of matr
ix deposition, which was attributed to a dominant-negative effect of mutant
molecules. For genotype/phenotype comparisons, clinical data on 25 proband
s and 19 mutation-positive family members were analyzed. Ocular manifestati
ons were among the most consistent features (ectopia lentis in 86%, myopia
in 80%). Nine mutations encoded by exons 26-32 resulted in early-onset clas
sic MFS and, in one case, neonatal-lethal MFS. Mutations outside this regio
n were associated with variable clinical phenotypes, including individuals
with fibrillinopathies not meeting diagnostic criteria for MFS.