Dm. Milewicz et al., A MUTATION IN FBN1 DISRUPTS PROFIBRILLIN PROCESSING AND RESULTS IN ISOLATED SKELETAL FEATURES OF THE MARFAN-SYNDROME, The Journal of clinical investigation, 95(5), 1995, pp. 2373-2378
Dermal fibroblasts from a 13-yr-old boy with isolated skeletal feature
s of the Marfan syndrome were used to study fibrillin synthesis and pr
ocessing, Only one half of the secreted profibrillin was proteolytical
ly processed to fibrillin outside the cell and deposited into the extr
acellular matrix, Electron microscopic examination of rotary shadowed
microfibrils made by the proband's fibroblasts were indistinguishable
from control cells, Sequencing of the FBN1 gene revealed a heterozygou
s C to T transition at nucleotide 8176 resulting in the substitution o
f a tryptophan for an arginine (R2726W), at a site immediately adjacen
t to a consensus sequence recognized by a cellular protease. Six other
individuals in the proband's family had the FBN1 mutation that segreg
ated with tall stature, None of the affected individuals have cardiac
or ocular manifestations of the Marfan syndrome, This mutation identif
ies a putative site for profibrillin to fibrillin processing, and is a
ssociated with isolated skeletal features of the Marfan syndrome, indi
cating that the FBN1 gene is one of the genes that determines height i
n the general population, The cellular effect of the mutation may be e
quivalent to a ''null'' FBN1 allele and may define the phenotype assoc
iated with FBN1 ''null'' alleles.