Prevalence of type 2b ‘Malmö/New York’ von Willebrand disease in Italy: the role of von Willebrand factor gene conversion

Baronciani, Luciano; Federici, Augusto B.; Castaman, Giancarlo; Punzo, Margherita; Mannucci, Pier Mannuccio

doi:10.1111/j.1538-7836.2008.02941.x

Cited by 14 publications

(8 citation statements)

References 22 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, this mutation has been reported (27) in three unrelated families from India. The discovery of this large gene conversion in four unrelated families supports the idea that the gene conversion mutation event in VWF is a fairly common occurrence (28,29).…”

Section: What Does This Paper Add?supporting

confidence: 64%

Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene

Corrales

Ramı́rez²,

Altisent³

et al. 2009

Thromb Haemost

View full text Add to dashboard Cite

SummaryMolecular diagnosis of von Willebrand Disease (VWD) is particularly complex. The autosomal von Willebrand factor gene (VWF) is large and highly polymorphic, and there is a highly homologous (>96%) partial pseudogene in chromosome 22. Because of these difficulties, application of molecular study of VWD to the clinical routine has been considerably delayed. Recent advances in sequencing technology and bioinformatics could convert direct sequencing of the complete VWF into a routine diagnostic tool for VWD, which is especially desirable in types 1 and 3. This study describes a highly optimized procedure in which all the coding and intronic flanking regions of VWF are amplified under identical thermocycling parameters in a ready-to-use PCR plate format. The entire sequencing procedure, from blood extraction to mutation identification, can be done within 24 hours, resulting in a simple, versatile, cost-effective strategy with little hands-on time requirements. To validate the method, we performed full-length VWF sequencing of 21 index cases including seven of each VWD type. A total of 30 VWF genetic variations were identified. Twelve of these sequence variations are new, including four missense, one nonsense, one insertion, the first insertion-deletion described in VWF, and 5 potential splice site mutations. To our knowledge, this is the fastest and most efficient protocol designed to date for complete sequencing of the VWF coding region in the molecular diagnosis of VWD.

show abstract

Section: What Does This Paper Add?supporting

confidence: 64%

Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene

Corrales

Ramı́rez²,

Altisent³

et al. 2009

Thromb Haemost

View full text Add to dashboard Cite

show abstract

“…The association of the P1226L substitution and 3789 G>A polymorphism was recently reported in a case of VWF gene conversion with the pseudogene. This family presents the same phenomenon as the family B described in this study [5]. Moreover, in vitro mutagenesis analysis confirms the relationship between this mutation and enhanced interaction with platelets in the presence of ristocetin [6].…”

supporting

confidence: 82%

Contribution of genetical analysis for diagnosis of von Willebrand’s disease type 2B

et al. 2009

View full text Add to dashboard Cite

“…Moreover, we could recently show that both mutations P1266L/Q are associated with VWD2B Malmö/New York phenotype and that both mutations are the result of gene conversion between the VWF gene and its pseudogene. 34 The finding of a bleeding score higher than 4 in several members of families with mutations localized at position 1266 as well as the demonstration of enhanced interaction with GpIb-␣ of this P1266L VWF mutant 35 makes the hypothesis of a polymorphism improbable. Specific amino acid substitutions are probably critical for some VWD2B phenotypes: 12 of 16 patients with normal multimers, no thrombocytopenia but increased RIPA have substitutions with leucine at positions P1266 and R1308.…”

Section: Discussionmentioning

confidence: 99%

“…The following nucleotide changes were identified: 3692AϾC (N1231T), 3789GϾA, 3797CϾA (P1266Q) in families 1 and 2, 3686TϾG (V1229G), 3692AϾC (N1231T), 3735GϾA, 3789GϾA, 3797CϾT (P1266L) in family 3, and 3789GϾA, 3797CϾT (P1266L) in family 4, indicating gene conversion with pseudogene. 34 The data of these 16 patients are given in detail in Table 3: none of these patients characterized by enhanced RIPA, normal multimers, normal baseline platelet count, and morphology had increased values of VWF-GPIb-␣/BC (median ratio, 0.59; range, 0.32-1.09), as shown in Figure 5A,B. Eight of these patients underwent a stress situation during follow-up without developing thrombocytopenia.…”

Section: Vwd2b Patients With Normal Multimeric Pattern and Platelet Cmentioning

confidence: 97%

Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients

Federici

Mannucci

Castaman

et al. 2009

Blood

234

308

View full text Add to dashboard Cite

Type 2B von Willebrand disease (VWD2B)is caused by an abnormal von Willebrand factor (VWF) with increased affinity for the platelet receptor glycoprotein Ib-␣ (GPIb-␣) that may result in moderate to severe thrombocytopenia. We evaluated the prevalence and clinical and molecular predictors of thrombocytopenia in a cohort of 67 VWD2B patients from 38 unrelated families characterized by VWF mutations. Platelet count, mean platelet volume, and morphologic evaluations of blood smear were obtained at baseline and during physiologic (pregnancy) or pathologic (infections, surgeries) stress conditions. Thrombocytopenia was found in 20 patients (30%) at baseline and in 38 (57%) after stress conditions, whereas platelet counts were always normal in 16 patients (24%) from 5 families carrying the P1266L/Q or R1308L mutations. VWF in its GPIb-␣-binding conformation (VWFGPIb-␣/BC) was higher than normal in all except the 16 cases without thrombocytopenia (values up to 6-fold higher than controls). The risk of bleeding was higher in patients with thrombocytopenia (adjusted hazard ratio ‫؍‬ 4.57; 95% confidence interval, 1.17-17.90) and in those with the highest tertile of bleeding severity score (5.66; 95% confidence interval, 1.03-31.07). Prediction of possible thrombocytopenia in VWD2B by measuring VWF-GPIb-␣/BC is important because a low platelet count is an independent risk factor for bleeding. (Blood. 2009;113: 526-534)

show abstract

Prevalence of type 2b ‘Malmö/New York’ von Willebrand disease in Italy: the role of von Willebrand factor gene conversion

Cited by 14 publications

References 22 publications

Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene

Rapid molecular diagnosis of von Willebrand disease by direct sequencing. Detection of 12 novel putative mutations in VWF gene

Contribution of genetical analysis for diagnosis of von Willebrand’s disease type 2B

Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients

Contact Info

Product

Resources

About