Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V-factor VIII deficiency
| Autor: | Stylianos E. Antonarakis, William C. Nichols, David Ginsburg, Flora Peyvandi, Colette Rossier, Marguerite Neerman-Arbez, Edward G. D. Tuddenham, John H. McVey, Michael A. Morris, K. M. Johnson |
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| Jazyk: | angličtina |
| Rok vydání: | 1999 |
| Předmět: |
Male
Candidate gene DNA Mutational Analysis Ethnic Groups/genetics Algeria/ethnology Factor V Deficiency/complications/ethnology/ genetics Iran Great Britain/ethnology Biochemistry Pakistan/ethnology South Africa Exon Consanguinity Jews/genetics Membrane Proteins/deficiency/ genetics Ethnicity Pakistan Italy/ethnology Polymorphism Single-Stranded Conformational Genetics ddc:616 Splice site mutation biology South Africa/ethnology Factor V Hematology Italy Allelic heterogeneity Female Factor V Deficiency China Hemophilia A/complications/ethnology/ genetics Immunology Locus (genetics) Genes Recessive Hemophilia A China/ethnology Codon/genetics Humans Allele Codon Gene Alleles Membrane Proteins Cell Biology United Kingdom Iran/ethnology Mannose-Binding Lectins Haplotypes Algeria Jews Mutation biology.protein |
| Zdroj: | Blood, Vol. 93, No 7 (1999) pp. 2253-2260 Scopus-Elsevier Europe PubMed Central |
| ISSN: | 0006-4971 |
| Popis: | Combined factor V-factor VIII deficiency (F5F8D) is a rare, autosomal recessive coagulation disorder in which the levels of both coagulation factors V and VIII are diminished. The F5F8D locus was previously mapped to a 1-cM interval on chromosome 18q21. Mutations in a candidate gene in this region, ERGIC-53, were recently found to be associated with the coagulation defect in nine Jewish families. We performed single-strand conformation and sequence analysis of the ERGIC-53 gene in 35 F5F8D families of different ethnic origins. We identified 13 distinct mutations accounting for 52 of 70 mutant alleles. These were 3 splice site mutations, 6 insertions and deletions resulting in translational frameshifts, 3 nonsense codons, and elimination of the translation initiation codon. These mutations are predicted to result in synthesis of either a truncated protein product or no protein at all. This study revealed that F5F8D shows extensive allelic heterogeneity and all ERGIC-53 mutations resulting in F5F8D are “null.” Approximately 26% of the mutations have not been identified, suggesting that lesions in regulatory elements or severe abnormalities within the introns may be responsible for the disease in these individuals. In two such families, ERGIC-53 protein was detectable at normal levels in patients’ lymphocytes, raising the further possibility of defects at other genetic loci. |
| Databáze: | OpenAIRE |
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