Mutations in the D1 domain of von Willebrand factor impair their propeptide-dependent multimerization, intracellular trafficking and secretion

Yin, Jing; Ma, Zhengliang; Su, Jian; Wang, Jiong‐Wei; Zhao, Xiaojuan; Ling, Jing; Bai, Xia; Ouyang, Wanyan; Wang, Zhaoyue; Yu, Ziqiang; Ruan, Changgeng

doi:10.1186/s13045-015-0166-9

Cited by 11 publications

(11 citation statements)

References 8 publications

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“…12,16,26,27 This might be due to the high rate of consanguinity in our cohort, and a subsequently greater likelihood of homozygosity for missense mutations. [30][31][32] On the other hand, the molecular mechanism of the mutations located in A domains (A1, A2, and A3) and D4 by which impair the total biosynthesis of VWF is remained to be understood by further gene expression analysis. It can be expected that mutations in C-terminal domains (C1 and CK) and propeptide region (D1 and D2) may interfere with dimerization and polymerization of VWF monomers, respectively.…”

Section: In Silico Structural Analysismentioning

confidence: 99%

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Ahmed

Yadegari²,

Naz

et al. 2019

Haemophilia

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Introduction Type 3 von Willebrand disease (VWD), a severe autosomal recessive hereditary bleeding disorder, is described by the virtual absence of von Willebrand factor (VWF). In consanguineous populations, for example Pakistan, the disease is reported with a higher incidence rate than the worldwide prevalence. Aims This study aims to characterize molecular pathology and clinical profile of type 3 VWD cohort of Pakistani origin. Methods In total, 48 patients were enrolled in the current study. Initially, the index patients (IPs) were evaluated by a standardized questionnaire for recording bleeding manifestations and by performing conventional coagulation tests. The diagnosis of VWD type 3 was confirmed by VWF antigens less than 5 IU/dL. Direct sequencing of VWF gene (VWF) was carried out to identify causative gene variations. We evaluated the potential consequence of novel splice site and missense variations by predictive computational programs and in silico structural analysis. Results VWF mutations were detected in 46 out of 48 IPs (95.8%), predominantly as homozygous variants. In total, twenty‐nine different gene defects were characterized in this cohort from which 10 (34.5%) are novel. The majority of the mutations were null alleles (66%; including gene conversions, nonsense, splice site variations, small deletions and insertions), and 34% of them were missense substitutions. Conclusion Herein, we reported for the first time, the pattern of gene defects in Pakistani type 3 VWD cohort. We identified a wide heterogeneous mutation spectrum along with variability in the type of bleeding episodes.

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Section: In Silico Structural Analysismentioning

confidence: 99%

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Ahmed

Yadegari²,

Naz

et al. 2019

Haemophilia

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“…Structural analysis was performed for only 4 mutations, while other missense changes were analysed using in silico analysis tools. Previously reported mutations (n = 6) were considered disease causative 30,[32][33][34][35][36] (Table 1).…”

Section: Mutationsinpatientswithvwdmentioning

confidence: 99%

Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Elayaperumal

Fouzia

Biswas³

et al. 2018

Haemophilia

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“…Mutation p.Arg273Trp was proved to result in defective multimerisation and secretion of VWF (42). There are quite a few VWD-causing missense mutations located in the propeptide of VWF (43)(44)(45), indicating the essential role of propeptide in multimerisation, intracellular trafficking, and secretion.…”

Section: Vwfpp (%)mentioning

confidence: 99%

Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex® technique

Liang¹,

Qin²,

Ding³

et al. 2017

Thromb Haemost

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Von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency, heterogeneous laboratory phenotype and race specific distribution of mutations. The present study aimed to determine the correlation of genotype and phenotype in 200 Chinese individuals from 90 unrelated families with VWD. Next generation sequencing (NGS) of the whole coding VWF, copy number analysis of VWF by CNVplex technique as well as a comprehensive phenotypic assessment were carried out in all index patients (IPs). We identified putative mutations in all IPs except five mild type 1 (85/90, 94.4 %). In total, 98 different mutations were detected, 62 (63.3 %) of which were reported for the first time (23 missense mutations, 1 regulatory mutation, 12 splice site mutations and 26 null mutations). Mutations p.Ser1506Leu and p.Arg1374His/Cys/Ser were the most frequent mutations in 2A (33 % of cases) and 2M VWD (67 % of cases), respectively. In addition, mutation p.Arg816Trp was detected repeatedly in type 2N patients, while mutation p.Arg854Gln, extremely common in Caucasians, was not found in our cohort. Thirty-three patients had two or more putative mutations. Unlike most cases of type 1 and type 2 VWD, which were transmitted dominantly, we presented seven severe type 1, two type 2A and one type 2M with autosomal recessive inheritance. Here the phenotypic data of patients with novel mutations will certainly contribute to the better understanding of the molecular genetics of VWF-related phenotypes.

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Mutations in the D1 domain of von Willebrand factor impair their propeptide-dependent multimerization, intracellular trafficking and secretion

Cited by 11 publications

References 8 publications

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Characterization of the mutation spectrum in a Pakistani cohort of type 3 von Willebrand disease

Type‐3 von Willebrand disease in India—Clinical spectrum and molecular profile

Molecular and clinical profile of VWD in a large cohort of Chinese population: application of next generation sequencing and CNVplex® technique

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