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Titolo:
2 MUTATIONS IN EXON-XII OF THE PROTEIN S-ALPHA GENE IN 4 THROMBOPHILIC FAMILIES RESULTING IN PREMATURE STOP CODONS AND DEPRESSED LEVELS OF MUTATED MESSENGER-RNA
Autore:
ANDERSEN BD; LIND B; PHILIPS M; HANSEN AB; INGERSLEV J; THORSEN S;
Indirizzi:
RIGSHOSP,DEPT CLIN BIOCHEM KB 3011,SECT HEMOSTASIS & TROMBOSIS,BLEGDAMSVEJ 9 DK-2100 COPENHAGEN DENMARK ODENSE UNIV HOSP,DEPT CLIN CHEM ODENSE DENMARK AARHUS UNIV HOSP,DEPT CLIN IMMUNOL AARHUS DENMARK
Titolo Testata:
Thrombosis and haemostasis
fascicolo: 2, volume: 76, anno: 1996,
pagine: 143 - 150
SICI:
0340-6245(1996)76:2<143:2MIEOT>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
DEFICIENCY TYPE-I; MESSENGER-RNA; NONSENSE MUTATION; C4B-BINDING PROTEIN; POINT MUTATIONS; FACTOR-V; HEREDITARY-DEFICIENCY; VENOUS THROMBOSIS; RISK FACTOR; PS-ALPHA;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
45
Recensione:
Indirizzi per estratti:
Citazione:
B.D. Andersen et al., "2 MUTATIONS IN EXON-XII OF THE PROTEIN S-ALPHA GENE IN 4 THROMBOPHILIC FAMILIES RESULTING IN PREMATURE STOP CODONS AND DEPRESSED LEVELS OF MUTATED MESSENGER-RNA", Thrombosis and haemostasis, 76(2), 1996, pp. 143-150

Abstract

Sixteen Danish unrelated thrombophilic families with plasma protein Sdeficiency of type I (or III) are currently under investigation in our laboratory for defects in the protein S alpha gene, The present paper describes a part of this work, which deals with the identification and phenotypical presentation of two unique mutations in exon XII of the protein S alpha gene in four of these families. The mutations were identified by SSCP screening followed by nucleotide sequence analysis or by direct nucleotide sequence analysis. The mutation found in one family (D) is a novel deletion of an A in either the codon for Gly(448) (GGA) or Ile(449) (ATT) resulting in a frameshift and a premature stopcodon at position 454. The other mutation shared by three families (F, G and J) is a previously reported C --> T transition within a hypermutable CG dinucleotide sequence converting Arg(410) (CGA) to Stop (TGA). All affected individuals are heterozygotes for their mutation and in each family the protein S genotype, the plasma protein S phenotype (not shown for Family J) and the clinical phenotype cosegregate, The two mutations can fully explain the abnormal protein S phenotype since premature stop codons are known to disrupt gene function of the mutatedallele. Analysis of protein S mRNA from platelets showed that both mutations result in a marked reduction in the amount of protein S mRNA from the mutated alleles indicating that the mutations exert their deleterious effects on gene expression at the transcriptional level. The Arg(410) --> Stop mutation in Families F, G and J is in all instances linked to a G at the site of a common neutral dimorphism in the codon for Pro(626) (CCA-G) in exon XV. This indicates that the mutation in these families could have arisen in a common ancestor. The Arg(410) (CGA) --> Stop (TGA) mutation is also seen in exon XII of the normal protein S alpha gene, This gives rise to the speculation as to whether the mutation in the protein S alpha gene is the result of an interaction with the protein S beta gene leading to double homologous unequal crossing-over or gene conversion of a shea DNA sequence. However, this is unlikely since none of the 7 other protein S beta-specific nucleotides are present in the mutated exon XII sequence of the protein S alpha gene. The common Arg(506) --> Gln Leiden mutation in coagulation factor V is not an additional risk factor for thrombosis in any of the four families studied.

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Documento generato il 03/12/20 alle ore 15:56:48