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| ANALYSIS OF FACTOR-VIII MESSENGER-RNA REVEALS DEFECTS IN EVERYONE OF 28 HEMOPHILIA-A PATIENTS |
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| Author(s): NAYLOR JA, GREEN PM, RIZZA CR, GIANNELLI F |
| Source: HUMAN MOLECULAR GENETICS Volume: 2 Issue: 1 Pages: 11-17 Published: JAN 1993 |
| Times Cited: 123 References: 47 |
| Abstract: Haemophilia A is a mutationally heterogeneous disease caused by defects in the large and complex factor VIII gene. Recent studies examining the putative promoter, all exons and most intron/exon boundaries have failed to detect mutations in half the patients with severe disease leading to hypotheses such as mutations in remote controlling regions or even in genes other than factor VIII. We have amplified the factor VIII gene (putative promotor, coding region and polyadenylation/cleavage signal region) in 8 fragments from reverse transcribed mRNA and genomic DNA. Any mutation is then located by chemical mismatch detection and characterised by direct sequencing. This rapid and efficient method has been fully successful and has revealed an unusual cluster of mutations causing severe disease. Of the 28 patients we have reported, 5 had mild or moderate disease and all had a missense mutation. Twenty-three patients were severely affected and 13 of these had different detrimental mutations that were fully characterised at the genomic DNA level. The remaining 10 patients all had mRNA with exon 22 not contiguous to exon 23. Since all exons were normal and so were the splice sites of intron 22, the mutation in these patients should be in the regions of intron 22 that were not screened. These results prove that all haemophilia A cases are due to mutations of the factor VIII gene where, unexpectedly, intron 22 seems to be the target of approximately 40% of the mutations causing severe haemophilia A. |
| Document Type: Article |
| Language: English |
Addresses:
1. UNITED MED & DENT SCH GUYS & ST THOMASS HOSP, DIV MED & MOLEC GENET, 7TH FLOOR GUYS HOSP TOWER, LONDON SE1 9RT, ENGLAND
2. CHURCHILL HOSP, OXFORD HAEMOPHILIA CTR, OXFORD OX3 7LJ, ENGLAND |
| Publisher: OXFORD UNIV PRESS UNITED KINGDOM, WALTON ST JOURNALS DEPT, OXFORD, ENGLAND OX2 6DP |
| Subject Category: Biochemistry & Molecular Biology; Genetics & Heredity |
| IDS Number: KM980 |
| ISSN: 0964-6906 |
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