Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients

Baronciani, Luciano; Cozzi, Giovanna; Canciani, Maria Teresa; Peyvandi, Flora; Srivastava, Alok; Federici, Augusto B.; Mannucci, Pier Mannuccio

doi:10.1016/s1079-9796(03)00033-0

Cited by 102 publications

(123 citation statements)

References 37 publications

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“…The low frequency of these mutations occurring in correspondence of the CpG dinucleotide in this group of patients is consistent with previous reports [21][22][23][24][25][26][27]. CpG dinucleotides are hotspot for mutation in the human genome [28].…”

Section: Discussionsupporting

confidence: 92%

“…A total of 14 distinct mutations were identified. Ten of them were novel and although none of these mutations was found in more than one patient, three out of the four previously reported mutations have been identified in VWD3 Italian patients [21]. Five were deletions: two large ones (del exons 1-3, del exon 17) and three resulting in the loss of few nucleotides.…”

Section: Discussionmentioning

confidence: 88%

“…HRM analysis was then carried out for 25 exons (number 4,6,8,9,11,12,16,17,19,20,21,23,25,30,34,35,36,38,39,40,41,44,46,48,51) in all patients. This is a mutation scanning technique that monitors the progressive change in fluorescence caused by the release of an intercalating DNA dye from a DNA duplex as it is denatured with marginal increases in temperature [18].…”

Section: Mlpamentioning

confidence: 99%

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Molecular characterization, recombinant protein expression, and mRNA analysis of type 3 von Willebrand disease: Studies of an Italian cohort of 10 patients

et al. 2012

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Type 3 von Willebrand disease (VWD3) is characterized by unmeasurable von Willebrand factor (VWF) levels in plasma and platelets and severe but variable hemorrhagic symptoms. To identify and characterize the causal mutations, we screened 10 Italian patients with VWD3 by several techniques including Multiplex Ligation‐dependent Probe Amplification to identify large insertions and deletions, High Resolution Melting and PCR coupled with Sanger sequencing. Fourteen different mutations scattered throughout the VWF gene were identified, 10 of which were novel. As expected, most of these mutations caused null alleles: five were deletions (del exons 1–3, del exon 17, c.2157delA, c.2269delCT, and c.3940delG), three nonsense (p.Q1526X, p.E1549X, and p.C2448X) and three potential splice‐site mutations (c.658‐2A>G, c.7729+7C>T, and c.8155+1G>T). Three candidate missense mutations (p.C2184S, p.C2212R, and p.C2325S) were also identified. Missense mutations and the putative splice‐site defects were confirmed to be disease related by in vitro expression studies and mRNA analysis. None of these patients have developed alloantibodies against VWF. This study extends our previous finding that most of the mutations that we identified in VWD3 patients arise independently and are scattered throughout the entire VWF gene. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 88%

Section: Mlpamentioning

confidence: 99%

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Molecular characterization, recombinant protein expression, and mRNA analysis of type 3 von Willebrand disease: Studies of an Italian cohort of 10 patients

et al. 2012

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“…All FVIII/VWF measurements were expressed in international units (IU), with reference to a plasma pool standardized against the International Reference Preparation for FVIII/VWFrelated activities. The phenotypic distinction between VWD type 2A, 2B and 2M was also confirmed by DNA analysis of affected patients, as previously reported [15].…”

Section: Laboratory Assayssupporting

confidence: 85%

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees

Kunicki

Baronciani

Canciani

et al. 2006

Journal of Thrombosis and Haemostasis

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Summary. We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype -52T was associated with an increased bleeding severity score (P < 0.01). This association remained statistically significant when the three type 2B pedigrees were excluded (P ¼ 0.012) or when genderspecific bleeding categories were excluded (P < 0.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit a 2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.

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“…16 Type 3 VWD -81% to 100%. [17][18][19] 2.2 Analytical specificity (proportion of negative tests if the genotype is not present) Type 1 VWD -genetic testing not generally applicable (see 1.10 above). Types 2 and 3 VWD -genetic testing would be expected to be negative in the absence of the disease.…”

Section: Analytical Sensitivity (Proportion Of Positive Tests If the mentioning

confidence: 99%

Clinical utility gene card for: von Willebrand disease

et al. 2011

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Molecular defects in type 3 von Willebrand disease: updated results from 40 multiethnic patients

Cited by 102 publications

References 37 publications

Molecular characterization, recombinant protein expression, and mRNA analysis of type 3 von Willebrand disease: Studies of an Italian cohort of 10 patients

Molecular characterization, recombinant protein expression, and mRNA analysis of type 3 von Willebrand disease: Studies of an Italian cohort of 10 patients

An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees

Clinical utility gene card for: von Willebrand disease

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