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Titolo:
PREFERENTIAL PRE-MESSENGER-RNA UTILIZATION OF AN UPSTREAM CRYPTIC 5'-SPLICE-SITE CREATED BY A SINGLE-BASE DELETION MUTATION IN EXON-37 OF THE FBN-1 GENE
Autore:
GIBSON MA; ELLIS SL; ADES LC; HAAN E; CLEARY EG;
Indirizzi:
UNIV ADELAIDE,DEPT PATHOL ADELAIDE SA 5005 AUSTRALIA WOMENS & CHILDRENS HOSP,DEPT MED GENET ADELAIDE SA AUSTRALIA
Titolo Testata:
European journal of biochemistry
fascicolo: 1, volume: 256, anno: 1998,
pagine: 221 - 228
SICI:
0014-2956(1998)256:1<221:PPUOAU>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
ELASTIN-ASSOCIATED MICROFIBRILS; NEONATAL MARFAN-SYNDROME; NONSENSE MUTATIONS; FIBRILLIN-1 FBN1; GLYCOPROTEIN; RECOGNITION; DEFINITION; SELECTION; SEQUENCE; RNAS;
Keywords:
CRYPTIC SPLICING; EXON MUTATION; FIBRILLIN; MARFAN SYNDROME;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
40
Recensione:
Indirizzi per estratti:
Citazione:
M.A. Gibson et al., "PREFERENTIAL PRE-MESSENGER-RNA UTILIZATION OF AN UPSTREAM CRYPTIC 5'-SPLICE-SITE CREATED BY A SINGLE-BASE DELETION MUTATION IN EXON-37 OF THE FBN-1 GENE", European journal of biochemistry, 256(1), 1998, pp. 221-228

Abstract

A heterozygous deletion of a single base (A4704) from exon 37 of the fibrillin-1 gene was defined in a patient with Marfan syndrome and subsequently in his previously undiagnosed father. The deletion created acryptic 5' splice site in exon 37 which was utilised in preference tothe normal 5' splice site during pre-mRNA processing in skin fibroblasts cultured from the proband. The mutant mRNA showed a 48-bp deletionfrom the 3' end of exon 37 which was predicted to restore the readingframe in the mutant mRNA and result in the deletion of a 16-amino-acid sequence from a central eight-cysteine repeat motif of the fibrillin-1 molecule. Interestingly, the cryptic 5' splice site in exon 37 and the normal 5' splice site had equally strong consensuses for splice-site selection. The preferential utilisation of the cryptic site is discussed in relation to current theories on the mechanisms involved in pre-mRNA splicing. Analysis by reverse-transcription PCR indicated that,in the patients skin fibroblasts, the steady-state level of the mis-spliced mutant mRNA was close to that from the normal allele. In addition, evidence from immunoblotting and pulse-chase biosynthetic labelling indicated that close to normal amounts of fibrillin-1 were being synthesised and secreted by the cells. However, in contrast to control cells cultured from an unaffected individual, little fibrillin-1 was detected, either biosynthetically or by immunofluorescence, in the extracellular matrix produced by the proband's fibroblasts. Thus, the slightly shorter mutant fibrillin-1 molecules appeared to be exerting a powerful dominant-negative effect on the incorporation of normal fibrillin-1 molecules into microfibrils in this culture system. This severe inhibition of microfibril synthesis in cell culture contrasts with the 'classic' phenotype of the proband, suggesting that factors influencing microfibril formation may differ greatly between in vivo and in vitro environments.

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Documento generato il 15/08/20 alle ore 19:57:06