Molecular Defects in Hemophilia B

Thompson, Arthur R.

doi:10.1007/978-1-4615-3698-7_8

Cited by 3 publications

(6 citation statements)

References 76 publications

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“…Point mutations in hemophilia B patients; Seattle series. * C---~T or G---~A within a CG dinucleotide; + novel nucleotide change, not previously described in other series (see Thompson 1991) Yoshitake et al (1985) tron 1 insert present, TaqI negative and Thr-148, and HhaI positive (as found in 8% of Caucasian factor IX genes). Patients from the four families with the 296.1 change (Thr-to-Met) were the same phenotype except for being intron 1 insert absent and HhaI negative (as found in 22% of Caucasian factor IX genes).…”

Section: Resultsmentioning

confidence: 86%

“…Finally, a 4-bp deletion at a donor splice junction site was found. These seven mutations (and the 50 patients with point mutations) have been summarized (Thompson 1991). Overall, 50 of 57 patients (88% with defined mutations have had point mutations.…”

Section: Resultsmentioning

confidence: 98%

“…For the CG-type mutations, independent origins of the codon 333.1 (Arg to Stop) defect have been demonstrated by de novo occurrence in three families (Koeberl et al 1990a); the three patients in this series (two reported previously) also have distinct haplotypes (A. R. Thompson and S.-H. Chen, unpublished). In addition, different haplotypes of factor IX are associated in each of the three Dashed lines indicate numbers of mutations found in non-CG codons (from Thompson 1991), the majority of which represent different nucleotide substitutions families with the codon 60.1 (Gly-to-Ser) defect. The two patients each with the codons 233.1 (Ala-to-Thr) and 333.2 (Arg-to-Gln) defects had different ethnic and geographic origins as well as distinct haplotypes.…”

Section: Discussionmentioning

confidence: 98%

“…Mutations in the X-linked factor IX gene are responsible for deficient factor IX activity in patients with hemophilia B (Thompson 1991). Haldane (1935) proposed that each hemophilic family with an affected member would have its own "private" variant.…”

Section: Introductionmentioning

confidence: 99%

“…S. H. Chen, Department of Pediatrics, RD-20, University of Washington, Seattle, WA 98195, USA Genetic heterogeneity of hemophilia B is evident from multiple molecular defects of the factor IX gene in different patients. Defects include distinct gene deletions, insertions, and point mutations (Brownlee 1989;Thompson 1991). While gross gene deletions or insertions are easily detected during routine Southern blot analyses of patient's DNA, most point mutations and small nucleotide deletions (or insertions) can only be defined by DNA sequencing.…”

Section: Introductionmentioning

confidence: 99%

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CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series

et al. 1991

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Hemophilia B is due to multiple molecular defects in the factor IX gene. Over 80% of mutations are single base substitutions. By amplification and direct sequencing, 51 single base substitutions were found in the transcribed sequence of the factor IX genes of patients from 50 distinct families with hemophilia B. These include 30 mutations in 29 families not previously reported by us; of these, 12 are novel, i.e., not previously published in other series. Of the 51 substitutions in our overall series 23 (45%) occurred as C-to-T or G-to-A transitions at 11 sites within CG dinucleotides. It is estimated that CG transitions occur from one to two orders of magnitude more frequently than mutations in nucleotides that are not within a CG pair. More than one family had identical defects for 6 of the CG mutations. At 4 of these sites, most patients had different haplotypes compatible with distinct mutations. Non-CG-type mutations occurred throughout the coding regions with only one mutation in more than one family. The latter included 7 families with a 397 Ile-to-Thr defect that all share a rare haplotype, suggesting a common ancestor.

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Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series

et al. 1991

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Hereditary Protein C Deficiency Associated with Mutations in Exon IX of the Protein C Gene

1994

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SummaryThis report describes five families with symptomatic hereditary protein C deficiency. Using a polymerase chain reaction (PCR)-based method, the entire coding sequence and intron-exon boundaries of the protein C gene was amplified from genomic DNA. In each family a single point mutation in the protein C gene was identified. Two unrelated families were found to share the same mutation, while the other three had different mutations. In the first two families with type I protein C deficiency the normal cytosine residue at nucleotide position 8551 in the protein C gene was replaced by thymidine leading to substitution of the normal proline residue at amino acid position 279 by leucine. In the third family with type I deficiency a previously undescribed mutation was identified. In this family the guanosine residue at position 8559 was replaced by adenosine (glycine 282 substituted by serine). In the fourth family, also with type I deficiency, guanosine 8589 was replaced by adenosine (glycine 292 substituted by serine). The fifth family had type II deficiency and in affected members cytosine 8769 was replaced by thymidine (arginine 352 substituted by tryptophan). All these mutations lead to amino acid substitutions in the serine protease domain of the mature protein. All were able to be confirmed by restriction enzyme analysis of PCR-derived DNA. In addition the novel mutation at nucleotide position 8559 was also demonstrable using single strand conformation polymorphism (SSCP) analysis of PCR-derived DNA. These mutations were likely examples of deamination of methylated cytosine occurring in cytosine-phosphate-guanosine (CpG) dinucleotide sequences. These findings confirm the genetic heterogeneity of hereditary protein C deficiency in these families.

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Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations

Bovill

Tomczak

Grant

et al. 1992

Blood

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This study investigates type II protein C deficiency in a family with manifestations of both arterial and venous thrombosis. Of 64 members of the kindred, 14 have been tested and 7 have PC deficiency. Among affected individuals (n = 7), mean protein C levels by different assays were as follows: enzyme-linked immunosorbent assay (ELISA), 3.8 micrograms/mL (2.1 to 4.3 micrograms/mL); amidolytic with venom activator, 115% (60% to 140%); clotting with venom activator, 42% (23% to 59%). The mean ratio of clotting to amidolytic assays for the affected individuals was 0.37 compared with a normal range of 0.8 to 1.2. Thus, the affected individuals have normal total protein C and their activated protein C has a normal active site assessed by chromogenic substrate; however, they have markedly diminished clotting activity. Immunoassay and chromatography data suggested an abnormality of carboxylation in the gamma carboxyglutamic acid (Gla) domain. Polymerase chain reaction amplification and direct DNA sequencing of exon 2 from genomic DNA of affected individuals showed two nucleotide substitutions. One of the mutations (A----C) results in Glu20----Ala, thereby eliminating a site for vitamin K-dependent gamma-carboxylation. The other substitution (G----A) results in a Val34----Met mutation. DNA sequencing of the other exons from affected individuals has shown no further difference from that of the wild-type gene. The former mutation also removes a Bgl II restriction endonuclease site, which has allowed us to confirm the mutation in affected individuals by direct digestion and Southern hybridization of genomic DNA from family members. This is the first reported family with documented Gla domain mutations in the protein C gene.

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Molecular Defects in Hemophilia B

Cited by 3 publications

References 76 publications

CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series

CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series

Hereditary Protein C Deficiency Associated with Mutations in Exon IX of the Protein C Gene

Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations

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