Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

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RECERCAT Home > Universitat de Barcelona > IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer > Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) > View document

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dc.contributor.author	Hurtado, Begoña
dc.contributor.author	Muñoz Miralles, Xavier
dc.contributor.author	Mulero Roig, María Carmen
dc.contributor.author	Navarro Brugal, Gemma
dc.contributor.author	Domènech, Pere
dc.contributor.author	García de Frutos, Pablo
dc.contributor.author	Pérez Riba, Mercè
dc.contributor.author	Sala Serra, Núria
dc.date	2019-01-24T08:48:31Z
dc.date	2019-01-24T08:48:31Z
dc.date	2008-04
dc.date	2019-01-24T08:48:31Z
dc.identifier	0390-6078
dc.identifier	http://hdl.handle.net/2445/127570
dc.identifier	657976
dc.identifier.uri	http://hdl.handle.net/2445/127570
dc.description	Background The molecular mechanisms by which PROS1 mutations result in protein S deficiency are still unknown for many of the mutations, particularly for those that result in a premature termination codon. The aim of this study was to analyze the functional relevance on mRNA and protein expression of 12 natural PROS1 mutations associated with protein S deficiency. Design and Methods Five mutations were nonsense, three were small frameshift deletions, one was c.258,259AG>GT at the 3' end of exon 3, one was p.M640T and the last two were c.-7C>G and p.L15H, found in double heterozygosis as [c.-7C>G;44T>A].The apparently neutral variant p.R233K was also analyzed. PROS1 cDNA was assessed by reverse transcriptase polymerase chain reaction of platelet mRNA. Expression of mutant proteins was determined by site-directed mutagenesis and analyses of transiently transfected PROS1 mutants in COS-7 cells. Results Only cDNA from the normal allele was observed from the five nonsense mutations, the frameshift deletion c.1731delT and from c.258,259AG>GT. Both the normal and the mutated alleles were observed from [c.-7C>G;44T>Aj, c.187,188delTG and p.M640T Transient expression analyses of PROS1 mutants whose mRNA was normally expressed revealed greatly reduced secretion of p.L15H and c.1272delA, mild secretion values of p.M640T and normal secretion levels of c.7C>G and, as expected, p.R233K. Conclusions Whereas the main cause of quantitative protein S deficiency associated with missense mutations is defective synthesis, stability or secretion of the mutated protein, the main mechanism for the deficiency associated with mutations that generate a premature termination codon is not the synthesis of a truncated protein, but the exclusion of the mutated allele, probably by nonsense-mediated mRNA decay.
dc.format	7 p.
dc.format	application/pdf
dc.language	eng
dc.publisher	Ferrata Storti Foundation
dc.relation	Reproducció del document publicat a: https://doi.org/10.3324/haematol.12090
dc.relation	Haematologica, 2008, vol. 93, num. 4, p. 574-580
dc.relation	https://doi.org/10.3324/haematol.12090
dc.rights	cc-by-nc (c) Ferrata Storti Foundation, 2008
dc.rights	http://creativecommons.org/licenses/by-nc/3.0/es
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Micro RNAs
dc.subject	Proteïnes recombinants
dc.subject	Mutagènesi
dc.subject	MicroRNAs
dc.subject	Recombinant proteins
dc.subject	Mutagenesis
dc.title	Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/publishedVersion

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