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Titolo:
Differential effect of FBN1 mutations on in vitro proteolysis of recombinant fibrillin-1 fragments
Autore:
Booms, P; Tiecke, F; Rosenberg, T; Hagemeier, C; Robinson, PN;
Indirizzi:
Humboldt Univ, Klinikum Charite, Lab Padiat Mol Biol, D-10098 Berlin, Germany Humboldt Univ Berlin Germany D-10098 t Mol Biol, D-10098 Berlin, Germany Natl Eye Clin Visually Impaired, Hellerup, Denmark Natl Eye Clin Visually Impaired Hellerup Denmark red, Hellerup, Denmark
Titolo Testata:
HUMAN GENETICS
fascicolo: 3, volume: 107, anno: 2000,
pagine: 216 - 224
SICI:
0340-6717(200009)107:3<216:DEOFMO>2.0.ZU;2-7
Fonte:
ISI
Lingua:
ENG
Soggetto:
FACTOR-LIKE DOMAINS; ABDOMINAL AORTIC-ANEURYSMS; NEONATAL MARFAN-SYNDROME; EGF-LIKE DOMAIN; MATRIX METALLOPROTEINASES; CALCIUM; BINDING; GENE; MICROFIBRILS; DEGRADATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Robinson, PN Humboldt Univ, Klinikum Charite, Lab Padiat Mol Biol, Ziegelstr 5-9, D-10098 Berlin, Germany Humboldt Univ Ziegelstr 5-9 Berlin GermanyD-10098 , Germany
Citazione:
P. Booms et al., "Differential effect of FBN1 mutations on in vitro proteolysis of recombinant fibrillin-1 fragments", HUM GENET, 107(3), 2000, pp. 216-224

Abstract

Mutations in the fibrillin-1 gene (FBN1) cause Marfan syndrome (MFS), an autosomal dominant disorder of connective tissue with highly variable clinical manifestations. FBN1 contains 47 epidermal growth factor (EGF)-like modules, 43 of which display a consensus sequence for calcium binding (cbEGF). Calcium binding by cbEGF modules is thought to be essential for the conformation and stability of fibrillin-1. Missense mutations in cbEGF modules arethe most common mutations found in MFS and generally affect one of the sixhighly conserved cysteines or residues of the calcium-binding consensus sequence. We have generated a series of recombinant fibrillin-1 fragments containing six cbEGF modules (cbEGF nos. 15-20) with various mutations at different positions of cbEGF module no. 17, which is known to contain a crypticcleavage site for trypsin. A mutation affecting a residue of the calcium-binding consensus sequence (K1300E) found in a patient with relatively mild clinical manifestations of classic MFS caused a modest increase in susceptibility to in vitro proteolysis by trypsin, whereas a mutation affecting thesixth cysteine residue of the same cbEGF module (C1320S) reported in a severely affected patient caused a dramatic increase in susceptibility to in vitro proteolysis by trypsin. A mutation at the cryptic cleavage site for trypsin abolished sensitivity of wild-type fragments and fragments containingK1300E to trypsin proteolysis. Whereas the relevance of in vitro proteolysis to the in vivo pathogenesis of MFS remains unclear, our findings demonstrate that individual mutations in cbEGF modules can affect these modules differentially and may suggest an explanation for some genotype-phenotype relationships in MFS.

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Documento generato il 19/09/20 alle ore 11:32:01