Sublocalization of von Willebrand factor pseudogene to 22q11.22?q11.23 by in situ hybridization in a 46,X,t(X;22)(pter;q11.21) translocation

Patracchini, P.; Calzolari, Elisa; Aiello, Vincenzo; Palazzi, P.; Banin, P; Marchetti, Giovanna; Bernardi, Francesco

doi:10.1007/bf00285168

Cited by 34 publications

(13 citation statements)

References 32 publications

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“…In addition to the VWF gene, a partial unprocessed VWF pseudogene is located on human chromosome 22q11.2 (114). The pseudogene is 21 to 29 kb in length and corresponds to exons 22-34 of the VWF gene, which encode domains A1-A2-A3 (115).…”

Section: The Vwf Gene and Pseudogenementioning

confidence: 99%

Biochemistry and Genetics of Von Willebrand Factor

Sadler

1998

Annu. Rev. Biochem.

1,249

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Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical ≈250 kDa subunits into disulfide-linked multimers that may be >20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clincial symptoms and the response to therapy. CONTENTS

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Section: The Vwf Gene and Pseudogenementioning

confidence: 99%

Biochemistry and Genetics of Von Willebrand Factor

Sadler

1998

Annu. Rev. Biochem.

1,249

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“…The mRNA is 8.7 kb in size, coding for precursor protein of 2813 amino acids that includes a 22 amino acids signal peptide, a propeptide of 741 amino acids and a mature subunit of 2050 amino acids [3]. A partial unprocessed pseudogene ( VWFP ) spanning exons 23–34 has been localized to chromosome 22q11.22-q11.23 with 97% homology to VWF, which makes it difficult to detect mutations in these regions [4].…”

Section: Introductionmentioning

confidence: 99%

Genetic Heterogeneity in a Large Cohort of Indian Type 3 von Willebrand Disease Patients

2014

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BackgroundThough von Willebrand disease (VWD) is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF), not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy.MethodWe evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA).ResultsMutations could be characterized in 77 unrelated index cases (ICs). 59 different mutations i.e. nonsense 20 (33.9%), missense 13 (22%), splice site 4 (6.8%), gene conversions 6 (10.2%), insertions 2 (3.4%), duplication 1 (1.7%), small deletions 10 (17%) and large deletions 3 (5.1%) were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434*) and the other had a large deletion spanning exons 16–52.ConclusionThe molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients.

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“…This product comprises a signal peptide of 22 amino acids, a large pro‐peptide of 741 amino acids, and a mature VWF molecule containing 2050 amino acids. A non‐coding partial VWF pseudogene ( VWFP ) is present on chromosome 22 [10]. VWFP shows 97% homology with exons 23 to 34 of VWF , however the presence of multiple termination codons in the pseudogenic sequence indicates that it is not a functional gene.…”

Section: Introductionmentioning

confidence: 99%

The mutation spectrum associated with type 3 von Willebrand disease in a cohort of patients from the North West of England

et al. 2009

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Type 3 von Willebrand disease (VWD) is a severe autosomal recessive inherited bleeding disorder. In affected individuals the underlying von Willebrand factor gene (VWF) mutations frequently remain uncharacterized. The aim of this study was to investigate the molecular basis of type 3 VWD in patients (11 Caucasians and 9 of Asian origin) attending the haemophilia centres at Central Manchester NHS Trust. A combination of DNA sequencing of VWF genomic and complementary DNA was performed to identify mutations in the patient cohort. Fifteen different VWF mutations were identified at the genomic DNA level: two gene conversion events, three nonsense, three frameshift, one missense, two splice site, one insertion-deletion and three deletion mutations. Homozygosity or compound heterozygosity for mutations was present in 15 of the 20 patients. In the remaining five individuals, heterozygosity for a single VWF mutation was identified in four cases and one patient had no detectable VWF mutation. Analysis of platelet-derived VWF RNA from these five individuals revealed heterozygosity for a deletion of exons 4 and 5 in four cases. The remaining patient was heterozygous for a three base deletion which had already been identified at the DNA level. Overall the observed VWF genotype explained the phenotype in 18 of the 20 patients investigated. In genetic studies in type 3 VWD, if VWF mutations are not detected at the DNA level, RNA analysis should be performed to search for intronic mutations, heterozygous deletions or aberrant splicing/post-transcriptional events. However, this may still not explain all cases of previously phenotypically diagnosed type 3 VWD.

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Sublocalization of von Willebrand factor pseudogene to 22q11.22?q11.23 by in situ hybridization in a 46,X,t(X;22)(pter;q11.21) translocation

Cited by 34 publications

References 32 publications

Biochemistry and Genetics of Von Willebrand Factor

Biochemistry and Genetics of Von Willebrand Factor

Genetic Heterogeneity in a Large Cohort of Indian Type 3 von Willebrand Disease Patients

The mutation spectrum associated with type 3 von Willebrand disease in a cohort of patients from the North West of England

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