Carrier Detection in Severe (Type III) von Willebrand Disease Using Two Intragenic Restriction Fragment Length Polymorphisms

Bahnak, Bruce R.; Lavergne, Jean‐Maurice; Verweij, CL; Rothschild, Cynthia B.; Pannekoek, Hans; Larrieu, M.J.; Meyer, Dominique

doi:10.1055/s-0038-1647025

Cited by 25 publications

(6 citation statements)

References 27 publications

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“…Three of our patients are homozygous for this allele, whereas, based on the frequency of the allele in our own as well as in the reported control populations (Lavergne et al, 1987), the probability of being homozygous is less than 1%. A patient with severe vWD who has been described by Bahnak et al(1988) was also homozygous for this 3 6 kb Xba I allele. Two of our six patients were heterozygous for the allele.…”

Section: Discussionmentioning

confidence: 97%

“…5-10 pg of DNA was digested to completion with XbaI. Southern blotting, nick translation and autoradiography were performed as described (Verweij et al, 1988). The probe employed was an approximately 1100 bp PstI vWF-cDNA fragment derived from pvWF 2280 (Verweij et al, 1985a).…”

Section: Methodsmentioning

confidence: 99%

“…1987;Lavergne et al, 1987;Bernardi et al, 1988). Using some of these RFLP we have been able to establish linkage between the vWF locus and type IIa vWD (Verweij et al, 1988).…”

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confidence: 99%

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An infrequent DNA polymorphism associated with severe von Willebrand's disease

1990

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Genomic DNA of six unrelated Dutch patients with severe von Willebrand's disease (vWD) was submitted to restriction fragment length polymorphism analysis. We observed a strong association between a 36 kb allele detected by a partial complementary DNA probe (pvWF 1100) and the restriction enzyme XbaI with severe von Willebrand's disease. This 36 kb allele is rare (allele frequency of 7%) both in the general population and in patients with autosomal dominant types of von Willebrand's disease. Three of our six patients were found to be homozygous for this allele while two others were heterozygous. The association of this rare XbaI allele with severe vWD enables carrier detection and prenatal diagnosis in these families. The high frequency (67%) of the 36 kb allele observed in this patient group raises the possibility that a subgroup of patients with severe vWD has a genetic defect with a common origin.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

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An infrequent DNA polymorphism associated with severe von Willebrand's disease

1990

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“…Polymerase chain reaction. The techniques for extraction of DNA from peripheral blood leucocytes and amplification of the genomic DNA by the polymerase chain reaction (PCR) (Saiki et al, 1988) have been described previously (Bahnak et al, 1988: Ribba et d. 1991. Approximately 1 pg of genomic DNA was amplified in a reaction volume of 100 p1 with 50 pmol of oligonucleotide primers.…”

Section: Patientsmentioning

confidence: 99%

Defects in type IIA von Willebrand disease: a cysteine 509 to arginine substitution in the mature von Willebrand factor disrupts a disulphide loop involved in the interaction with platelet glycoprotein Ib‐IX

et al. 1992

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Type IIA von Willebrand disease (vWD) is characterized by the loss of high and intermediate weight multimers of von Willebrand factor (vWF) from plasma. The 3' end of exon 28 in the vWF gene from four type IIA vWD patients was amplified by the polymerase chain reaction, cloned and sequenced. Sequencing identified two potential missense mutations resulting in the amino acid substitutions Arg 834-->Gln and Glu 875-->Lys in the mature vWF subunit within an area of vWF where mutations in type IIA vWD have been reported. Neither of these amino acid substitutions was found in over 100 normal alleles tested by allele specific oligonucleotide hybridization. A polymorphism (Val 802-->Leu) was identified in another patient. Other areas of exon 28 were analysed by denaturing gradient gel electrophoresis (DGGE) and DNA from one patient demonstrated an irregular DGGE pattern on the 5' end of the exon. Sequencing demonstrated an amino acid substitution of an arginine for cysteine at position 509 adjacent to an area of vWF where defects associated with type IIB vWD have been found. This substitution was not found in 100 normal chromosomes tested by restriction enzyme digestion. The Cys 509-->Arg substitution eliminates an intramolecular disulphide bridge formed by Cys 509 and Cys 695 which is important to maintain the configuration of vWF functional domains that interact with platelet glycoprotein Ib-IX.

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“…Given the complex multistep biosynthesis and processing of vWF, defects at a number of loci outside of the vWF gene could conceivably result in similar vWD phenotypes. All genetic linkage studies in vWD to date, however, have been consistent with defects within the vWF gene (16)(17)(18)(19)(20). In addition, missense mutations within the vWF gene have recently been reported in a qualitative variant of vWD, type IIA (21).…”

Section: Introductionmentioning

confidence: 99%

Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: detection by exonic PCR-restriction fragment length polymorphism analysis.

Nichols

Lyons

Harrison

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACTvon Willebrand disease (vWD), the most common inherited bleeding disorder in humans, results from abnormalities in the plasma clotting protein von Willebrand factor (vWF). Severe (type HI) vWD is autosomal recessive in inheritance and is associated with extremely low or undetectable vWF levels. We report a method designed to distinguish mRNA expression from the two vWF alleles by PCR analysis of peripheral blood platelet RNA using DNA sequence polymorphisms located within exons of the vWF gene. This approach was applied to a severe-vWD pedigree in which three of eight siblings are affected and the parents and additional siblings are clinically normal. Each parent was shown to carry a vWF allele that is silent at the mRNA level. Family members inheriting both abnormal alleles are affected with severe vWD, whereas individuals with only one abnormal allele are asymptomatic. The maternal and paternal silent alleles are identical at two coding sequence polymorphisms as well as an intron 40 variable number tandem repeat, suggesting a possible common origin. Given the frequencies of the two exon polymorphisms reported here, this analysis should be applicable to -70% of type I and type III vWD patients. This comparative DNA and RNA PCR-restriction fragment length polymorphism approach may also prove useful in identifying defects at the level of gene expression associated with other genetic disorders.

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Carrier Detection in Severe (Type III) von Willebrand Disease Using Two Intragenic Restriction Fragment Length Polymorphisms

Cited by 25 publications

References 27 publications

An infrequent DNA polymorphism associated with severe von Willebrand's disease

An infrequent DNA polymorphism associated with severe von Willebrand's disease

Defects in type IIA von Willebrand disease: a cysteine 509 to arginine substitution in the mature von Willebrand factor disrupts a disulphide loop involved in the interaction with platelet glycoprotein Ib‐IX

Severe von Willebrand disease due to a defect at the level of von Willebrand factor mRNA expression: detection by exonic PCR-restriction fragment length polymorphism analysis.

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