scholarly journals A de novo and heterozygous gene deletion causing a variant of von Willebrand disease

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 677-683
Author(s):  
F Bernardi ◽  
G Marchetti ◽  
S Guerra ◽  
A Casonato ◽  
D Gemmati ◽  
...  
Keyword(s):  
Gene Deletion ◽  
De Novo ◽  
Genomic Region ◽  
Restriction Pattern ◽  
Von Willebrand Disease ◽  
De Novo Mutation ◽  
Homologous Protein ◽  
Copy Dna ◽  
Von Willebrand ◽  
Reduced Intensity

An abnormal von Willebrand factor (vWF) gene restriction pattern has been found in a patient with von Willebrand disease. Because this gene alteration is not present in his parents or in 50 normal and 25 affected subjects, and the restriction fragment length polymorphism haplotypes are inherited normally in the patient's family, we suggest that a de novo mutation is present. Bands with reduced intensity and additional fragments, observed in several restriction digests, hybridize with noncontiguous copy DNA (cDNA) portions, thus indicating the presence of a heterozygous gene deletion. The deletion removes a genomic region containing at least codons 1147 through 1854 and corresponding to the D3-A3 homologous protein domains. The extent of the vWF pseudogene on chromosome 22 is roughly similar to that of the deleted area. However, the pseudogenic nature of the deletion is excluded by the mapping of bands with reduced intensity in the patient to the true vWF gene. The vWF antigen levels are one fourth of normal and ristocetin cofactor activity is severely impaired. The reduction of high molecular weight multimers in plasma and platelets and the altered triplet morphology are compatible with the presence of a dominant variant of type II von Willebrand disease.

scholarly journals A de novo and heterozygous gene deletion causing a variant of von Willebrand disease

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 677-683 ◽  
Author(s):  
F Bernardi ◽  
G Marchetti ◽  
S Guerra ◽  
A Casonato ◽  
D Gemmati ◽  
...  
Keyword(s):  
Gene Deletion ◽  
De Novo ◽  
Genomic Region ◽  
Restriction Pattern ◽  
Von Willebrand Disease ◽  
De Novo Mutation ◽  
Homologous Protein ◽  
Copy Dna ◽  
Von Willebrand ◽  
Reduced Intensity

Abstract An abnormal von Willebrand factor (vWF) gene restriction pattern has been found in a patient with von Willebrand disease. Because this gene alteration is not present in his parents or in 50 normal and 25 affected subjects, and the restriction fragment length polymorphism haplotypes are inherited normally in the patient's family, we suggest that a de novo mutation is present. Bands with reduced intensity and additional fragments, observed in several restriction digests, hybridize with noncontiguous copy DNA (cDNA) portions, thus indicating the presence of a heterozygous gene deletion. The deletion removes a genomic region containing at least codons 1147 through 1854 and corresponding to the D3-A3 homologous protein domains. The extent of the vWF pseudogene on chromosome 22 is roughly similar to that of the deleted area. However, the pseudogenic nature of the deletion is excluded by the mapping of bands with reduced intensity in the patient to the true vWF gene. The vWF antigen levels are one fourth of normal and ristocetin cofactor activity is severely impaired. The reduction of high molecular weight multimers in plasma and platelets and the altered triplet morphology are compatible with the presence of a dominant variant of type II von Willebrand disease.

scholarly journals Identification of three candidate mutations causing type IIA von Willebrand disease using a rapid, nonradioactive, allele-specific hybridization method

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 830-836 ◽  
Author(s):  
A Inbal ◽  
T Englender ◽  
N Kornbrot ◽  
AM Randi ◽  
G Castaman ◽  
...  
Keyword(s):  
De Novo ◽  
Screening Method ◽  
Von Willebrand Disease ◽  
Rapid Screening ◽  
De Novo Mutation ◽  
Platelet Glycoprotein ◽  
Missense Mutations ◽  
Hybridization Method ◽  
Allele Specific ◽  
Von Willebrand

Type IIA von Willebrand disease (vWD), the most common type II vWD variant, is characterized by decreased binding of von Willebrand factor (vWF) to platelet glycoprotein Ib (Gplb) and by a decrease in large and intermediate vWF multimers. Mutations reported to cause vWD type IIA are clustered within the A2 domain of vWF, which is encoded by exon 28. Genomic DNA from affected members of 12 unrelated families with type IIA vWD were screened for these mutations by a rapid, nonradioactive, allele-specific oligonucleotide (ASO) hybridization method. Oligonucleotides containing each of eight mutations were cross-linked onto a nylon membrane by UV irradiation. A fragment of vWF exon 28 was amplified from peripheral blood leukocyte DNA using biotinylated primers and hybridized to the immobilized oligonucleotides. Positive signals were detected with an avidin-alkaline phosphatase conjugate and chemiluminescent substrate. Thus, in a single hybridization reaction, a patient sample could be analyzed for a large number of mutations simultaneously. Polymerase chain reaction (PCR) products from four patients did not contain any of the tested mutations and therefore were sequenced. Three additional candidate missense mutations, two of them novel, were identified: Arg(834)-->Gln in one patient, Gly(846)-->Arg in one patient, and Val(902)-->Glu in three ostensibly unrelated patients. By ASO hybridization, the mutations were confirmed in the affected patients and excluded in unaffected relatives and 50 normal controls. In one family, the Val(902)-->Glu mutation was shown to be a de novo mutation. This rapid screening method is applicable to other subtypes of vWD for which mutations have been identified.

De novo mutation of the platelet glycoprotein Ib?? gene in a patient with pseudo-von Willebrand disease

1997 ◽  
Vol 8 (5) ◽  
pp. 311-315 ◽  
Author(s):  
S. Kunishima ◽  
D. C. Heaton ◽  
T. Naoe ◽  
C. Hickton ◽  
S. Mizuno ◽  
...  
Keyword(s):  
De Novo ◽  
Von Willebrand Disease ◽  
De Novo Mutation ◽  
Platelet Glycoprotein ◽  
Glycoprotein Ib ◽  
Von Willebrand

scholarly journals Identification of three candidate mutations causing type IIA von Willebrand disease using a rapid, nonradioactive, allele-specific hybridization method

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 830-836 ◽  
Author(s):  
A Inbal ◽  
T Englender ◽  
N Kornbrot ◽  
AM Randi ◽  
G Castaman ◽  
...  
Keyword(s):  
De Novo ◽  
Screening Method ◽  
Von Willebrand Disease ◽  
Rapid Screening ◽  
De Novo Mutation ◽  
Platelet Glycoprotein ◽  
Missense Mutations ◽  
Hybridization Method ◽  
Allele Specific ◽  
Von Willebrand

Abstract Type IIA von Willebrand disease (vWD), the most common type II vWD variant, is characterized by decreased binding of von Willebrand factor (vWF) to platelet glycoprotein Ib (Gplb) and by a decrease in large and intermediate vWF multimers. Mutations reported to cause vWD type IIA are clustered within the A2 domain of vWF, which is encoded by exon 28. Genomic DNA from affected members of 12 unrelated families with type IIA vWD were screened for these mutations by a rapid, nonradioactive, allele-specific oligonucleotide (ASO) hybridization method. Oligonucleotides containing each of eight mutations were cross-linked onto a nylon membrane by UV irradiation. A fragment of vWF exon 28 was amplified from peripheral blood leukocyte DNA using biotinylated primers and hybridized to the immobilized oligonucleotides. Positive signals were detected with an avidin-alkaline phosphatase conjugate and chemiluminescent substrate. Thus, in a single hybridization reaction, a patient sample could be analyzed for a large number of mutations simultaneously. Polymerase chain reaction (PCR) products from four patients did not contain any of the tested mutations and therefore were sequenced. Three additional candidate missense mutations, two of them novel, were identified: Arg(834)-->Gln in one patient, Gly(846)-->Arg in one patient, and Val(902)-->Glu in three ostensibly unrelated patients. By ASO hybridization, the mutations were confirmed in the affected patients and excluded in unaffected relatives and 50 normal controls. In one family, the Val(902)-->Glu mutation was shown to be a de novo mutation. This rapid screening method is applicable to other subtypes of vWD for which mutations have been identified.

scholarly journals Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 308-313 ◽  
Author(s):  
WF Bahou ◽  
EJ Bowie ◽  
DN Fass ◽  
D Ginsburg
Keyword(s):  
Von Willebrand Factor ◽  
Molecular Basis ◽  
Gene Deletion ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Von Willebrand Disease ◽  
Molecular Defect ◽  
Human Disorder ◽  
Von Willebrand ◽  
Willebrand Factor

von Willebrand disease (vWD), one of the most common bleeding disorders in humans, is manifested as a quantitative or qualitative defect in von Willebrand factor (vWF), an adhesive glycoprotein (GP) with critical hemostatic functions. Except for the rare severely affected patient with a gene deletion as etiology of the disease, the molecular basis for vWD is not known. We studied the molecular basis for vWD in a breeding colony of pigs with a disease closely resembling the human disorder. The porcine vWF gene is similar in size and complexity to its human counterpart, and no gross gene deletion or rearrangement was evident as the pathogenesis of porcine vWD. A restriction fragment- length polymorphism (RFLP) within the porcine vWF gene was identified with the restriction endonuclease HindIII, and 22/35 members of the pedigree were analyzed for the polymorphic site. Linkage between the vWF locus and the vWD phenotype was established with a calculated LOD score of 5.3 (1/200,000 probability by chance alone), with no crossovers identified. These findings indicate that porcine vWD is due to a molecular defect within (or near) the vWF locus, most likely representing a point mutation or small insertion/deletion within the vWF gene.

scholarly journals Phage Display Broadly Identifies Inhibitor-reactive Regions in von Willebrand Factor

2021 ◽  
Author(s):  
Andrew Yee ◽  
Manhong Dai ◽  
Stacy E. Croteau ◽  
Jordan A. Shavit ◽  
Steven W. Pipe ◽  
...  
Keyword(s):  
Phage Display ◽  
Von Willebrand Factor ◽  
Gene Deletion ◽  
Von Willebrand Disease ◽  
Response To Treatment ◽  
Phage Library ◽  
Incomplete Removal ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryBackgroundCorrection of von Willebrand factor (VWF) deficiency with replacement products containing VWF can lead to the development of anti-VWF alloantibodies (i.e., VWF inhibitors) in patients with severe von Willebrand disease (VWD).ObjectiveLocate inhibitor-reactive regions within VWF using phage display.MethodsWe screened a phage library displaying random, overlapping fragments covering the full length VWF protein sequence for binding to a commercial anti-VWF antibody or to immunoglobulins from three type 3 VWD patients who developed VWF inhibitors in response to treatment with plasma-derived VWF. Immunoreactive phage clones were identified and quantified by next generation DNA sequencing (NGS).ResultsNGS markedly increased the number of phage analyzed for locating immunoreactive regions within VWF following a single round of selection and identified regions not recognized in previous reports using standard phage display methods. Extending this approach to characterize VWF inhibitors from three type 3 VWD patients (including two siblings homozygous for the same VWF gene deletion) revealed patterns of immunoreactivity distinct from the commercial antibody and between unrelated patients, though with notable areas of overlap. Alloantibody reactivity against the VWF propeptide is consistent with incomplete removal of the propeptide from plasma-derived VWF replacement products.ConclusionThese results demonstrate the utility of phage display and NGS to characterize diverse anti-VWF antibody reactivities.

scholarly journals Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 308-313 ◽  
Author(s):  
WF Bahou ◽  
EJ Bowie ◽  
DN Fass ◽  
D Ginsburg
Keyword(s):  
Von Willebrand Factor ◽  
Molecular Basis ◽  
Gene Deletion ◽  
Molecular Genetic ◽  
Molecular Genetic Analysis ◽  
Von Willebrand Disease ◽  
Molecular Defect ◽  
Human Disorder ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand disease (vWD), one of the most common bleeding disorders in humans, is manifested as a quantitative or qualitative defect in von Willebrand factor (vWF), an adhesive glycoprotein (GP) with critical hemostatic functions. Except for the rare severely affected patient with a gene deletion as etiology of the disease, the molecular basis for vWD is not known. We studied the molecular basis for vWD in a breeding colony of pigs with a disease closely resembling the human disorder. The porcine vWF gene is similar in size and complexity to its human counterpart, and no gross gene deletion or rearrangement was evident as the pathogenesis of porcine vWD. A restriction fragment- length polymorphism (RFLP) within the porcine vWF gene was identified with the restriction endonuclease HindIII, and 22/35 members of the pedigree were analyzed for the polymorphic site. Linkage between the vWF locus and the vWD phenotype was established with a calculated LOD score of 5.3 (1/200,000 probability by chance alone), with no crossovers identified. These findings indicate that porcine vWD is due to a molecular defect within (or near) the vWF locus, most likely representing a point mutation or small insertion/deletion within the vWF gene.

scholarly journals Extraordinarily wide genomic impact of a selective sweep associated with the evolution of sex ratio distorter suppression

2014 ◽  
Author(s):  
Emily A Hornett ◽  
Bruce Moran ◽  
Louise A Reynolds ◽  
Sylvain Charlat ◽  
Samuel Tazzyman ◽  
...  
Keyword(s):  
Sex Ratio ◽  
Selective Sweep ◽  
De Novo ◽  
Purifying Selection ◽  
Genomic Region ◽  
De Novo Mutation ◽  
Rapid Spread ◽  
Before And After ◽  
Selective Forces ◽  
The Impact

Symbionts that distort their host?s sex ratio by favouring the production and survival of females are common in arthropods. Their presence produces intense Fisherian selection to return the sex ratio to parity, typified by the rapid spread of host ?suppressor? loci that restore male survival/development. In this study, we investigated the genomic impact of a selective event of this kind in the butterfly Hypolimnas bolina. Through linkage mapping we first identified a genomic region that was necessary for males to survive Wolbachia-induced killing. We then investigated the genomic impact of the rapid spread of suppression that converted the Samoan population of this butterfly from a 100:1 female-biased sex ratio in 2001, to a 1:1 sex ratio by 2006. Models of this process revealed the potential for a chromosome-wide selective sweep. To measure the impact directly, the pattern of genetic variation before and after the episode of selection was compared. Significant changes in allele frequencies were observed over a 25cM region surrounding the suppressor locus, alongside generation of linkage disequilibrium. The presence of novel allelic variants in 2006 suggests that the suppressor was introduced via immigration rather than through de novo mutation. In addition, further sampling in 2010 indicated that many of the introduced variants were lost or had reduced in frequency since 2006. We hypothesise that this loss may have resulted from a period of purifying selection - removing deleterious material that introgressed during the initial sweep. Our observations of the impact of suppression of sex ratio distorting activity reveal an extraordinarily wide genomic imprint, reflecting its status as one of the strongest selective forces in nature.

scholarly journals Autoimmune- and complement-mediated hematologic condition recrudescence following SARS-CoV-2 vaccination

2021 ◽  
Vol 5 (13) ◽  
pp. 2794-2798
Author(s):  
Andrew Jay Portuguese ◽  
Cassandra Sunga ◽  
Rebecca Kruse-Jarres ◽  
Terry Gernsheimer ◽  
Janis Abkowitz
Keyword(s):  
Hemophilia A ◽  
De Novo ◽  
Medical Center ◽  
Vaccine Dose ◽  
Von Willebrand Disease ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Acquired Von Willebrand Disease ◽  
Autoimmune Conditions ◽  
Von Willebrand

Abstract A variety of autoimmune disorders have been reported after viral illnesses and specific vaccinations. Cases of de novo immune thrombocytopenia (ITP) have been reported after SARS-CoV-2 vaccination, although its effect on preexisting ITP has not been well characterized. In addition, although COVID-19 has been associated with complement dysregulation, the effect of SARS-CoV-2 vaccination on preexisting complementopathies is poorly understood. We sought to better understand SARS-CoV-2 vaccine-induced recurrence of autoimmune- and complement-mediated hematologic conditions. Three illustrative cases were identified at the University of Washington Medical Center and the Seattle Cancer Care Alliance from January through March 2021. We describe the recrudescence of 2 autoimmune conditions (ITP and acquired von Willebrand Disease [AvWD]/acquired hemophilia A) and 1 complementopathy (paroxysmal nocturnal hemoglobinuria [PNH]). We report the first known case of AvWD/acquired hemophilia A, and describe the first PNH exacerbation in the absence of complement inhibition after SARS-CoV-2 vaccination. Although SARS-CoV-2 vaccine-induced ITP is a known concern, our case clearly depicts how thrombocytopenia in the setting of preexisting ITP can sequentially worsen with each vaccine dose. Based on our experiences and these examples, we provide considerations for how to monitor and assess risk in patients with underlying autoimmune- and complement-mediated hematologic conditions.

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