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- Green, P M, et al.
(författare)
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The incidence and distribution of CpG----TpG transitions in the coagulation factor IX gene. A fresh look at CpG mutational hotspots
- 1990
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 18:11, s. 31-3227
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Tidskriftsartikel (refereegranskat)abstract
- The mutations of 76 haemophilia B patients representing the whole population registered with the Malmö haemophilia centre (42) and referrals from the UK, were characterised. RFLP haplotype analysis of the defective genes indicated that 51 single base pair substitutions were definitely of independent origin and 27 of these were CpG----TpG or CpA transitions. This represents a 38-fold excess over other single-base changes. Most of such transitions (82%) occur at 9 CpG sites occupying critical positions (transitions at 3 sites substitute essential arginines, while at 6 sites transition to TpG creates stop codons). Sixteen of the 18 possible transitions at these 9 sites cause clear haemophilia B and should be fully ascertained in our haemophilia B population. This allowed the direct estimate of the rate of CpG transitions. This is 1.05 x 10(-7) substitutions per base per gamete per generation. The marked excess of CpG transitions in haemophilia B appears partly due to the high proportion of CpG sites at critical positions (at least 9 out of 20). We propose that this follows from the fact that male hemizygosity makes X-linked genes particularly susceptible to selective forces that tend to fix CpG sites arising at critical positions.
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| 3. |
- Montandon, A J, et al.
(författare)
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Two factor IX mutations in the family of an isolated haemophilia B patient : direct carrier diagnosis by amplification mismatch detection (AMD)
- 1990
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Ingår i: Human Genetics. - 0340-6717. ; 85:2, s. 4-200
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Tidskriftsartikel (refereegranskat)abstract
- Rapid identification of gene defects allows definite carrier and prenatal diagnosis in virtually every family with haemophilia B. We report a study of the family of an isolated patient. Analysis of all the essential regions of the patient's factor IX gene (promoter, exons, transcript processing signals) revealed two mutations: one C----T transition at residue 17762 and another at residue 30890. The former created a translation stop at codon 116, and the latter caused substitution of His 257 by Tyr. The translation stop is an obvious detrimental mutation, while the His 257----Tyr substitution has uncertain functional consequences. From analysis of other family members, it was found that the first mutation had occurred at grandpaternal gametogenesis, in keeping with the negative family history, while the second was of more remote origin and did not reduce the maternal grandfather's factor IX coagulant and antigen level. This neutral mutation (His 257----Tyr) pinpoints a poorly conserved amino acid in factor IX and related serine proteases. Its coexistence with a detrimental mutation stresses the need to examine all essential regions of a gene before attempting to interpret the functional consequences of its sequence changes.
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