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Titolo:
Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: Distinct effects on biochemical and clinical phenotypes
Autore:
Schrijver, I; Liu, W; Brenn, T; Furthmayr, H; Francke, U;
Indirizzi:
Stanford Univ, Sch Med, Med Ctr, Howard Hughes Med Inst, Stanford, CA 94305 USA Stanford Univ Stanford CA USA 94305 ghes Med Inst, Stanford, CA 94305 USA Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA Stanford UnivStanford CA USA 94305 , Dept Pathol, Stanford, CA 94305 USA Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA Stanford Univ Stanford CA USA 94305 d, Dept Genet, Stanford, CA 94305 USA
Titolo Testata:
AMERICAN JOURNAL OF HUMAN GENETICS
fascicolo: 4, volume: 65, anno: 1999,
pagine: 1007 - 1020
SICI:
0002-9297(199910)65:4<1007:CSIEGF>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEONATAL MARFAN-SYNDROME; EGF-LIKE DOMAINS; MISSENSE MUTATION; CALCIUM-BINDING; POINT MUTATIONS; PATHOGENETIC MECHANISMS; FBN1 MUTATIONS; GENE; EXONS; DISORDERS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
50
Recensione:
Indirizzi per estratti:
Indirizzo: Francke, U Stanford Univ, Sch Med, Med Ctr, Howard Hughes Med Inst, Stanford, CA 94305 USA Stanford Univ Stanford CA USA 94305 st, Stanford, CA 94305 USA
Citazione:
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

Abstract

Fibrillin-1 (FBN1) contains 47 epidermal growth factor (EGF)-like domains characterized by six conserved cysteine residues. Cysteine substitutions that disrupt one of the three disulfide bonds are frequent causes of Marfan syndrome (MFS). We identified 19 new substitutions involving cysteine residues in each of the six positions of EGF-like domains. Allele-specific mRNA assays revealed equal abundance of mutant and normal FBN1 transcripts in all10 individuals studied. Quantitative pulse-chase analysis of fibrillin protein was performed on 25 mutant fibroblast strains with substitutions of 22different cysteine residues in 18 different EGF-like domains spanning the entire gene. Normal synthesis and stability of mutant fibrillin molecules was seen in 20/25 individuals, 11 of whom showed delayed intracellular processing and/or secretion. In the remaining five cases, the mutant protein wasapparently unstable. In four of these five cases, the second or third disulfide bond of EGF-like domains immediately preceding an 8-cysteine or hybrid domain was affected. All but two mutations caused severe reduction of matrix deposition, which was attributed to a dominant-negative effect of mutant molecules. For genotype/phenotype comparisons, clinical data on 25 probands and 19 mutation-positive family members were analyzed. Ocular manifestations were among the most consistent features (ectopia lentis in 86%, myopiain 80%). Nine mutations encoded by exons 26-32 resulted in early-onset classic MFS and, in one case, neonatal-lethal MFS. Mutations outside this region were associated with variable clinical phenotypes, including individualswith fibrillinopathies not meeting diagnostic criteria for MFS.

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Documento generato il 19/09/20 alle ore 11:44:58