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Molecular Genetics in the Von Willebrand disease

Molecular Genetics in the Von Willebrand disease. Ghasem Rastegarlari. VON WILLEBRAND DISEASE VWD General definitions . The most frequent congenital bleeding disorder caused by defects of VWF: - quantitative = Types 1 & 3 VWD - qualitative = Type 2 VWD

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Molecular Genetics in the Von Willebrand disease

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  1. MolecularGenetics in the Von Willebranddisease Ghasem Rastegarlari

  2. VON WILLEBRAND DISEASE VWD General definitions • The most frequent congenital bleeding • disorder caused by defects of VWF: • - quantitative = Types 1 & 3 VWD • - qualitative = Type 2 VWD • Autosomal dominant/recessive pattern • Women are more symptomatic

  3. Von Willebrand disease Genetic aspect Human VWF Gene Chromosome 12 1 7 14 52 VWF (12p13.3) p 178 kb, 52 exons mRNA8.7 kb q

  4. 5’ 7 16 28 37 3’ bp 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 Multimers S-S Dimers S-S 1-23 163 2813 H2N COOH D1 D2 D’ D3 A1 A2 A3 D4 C1 C2 CK B1 Endothelial cells Platelets B2 FVIII RGD B3 IIb3 ENCODING REGIONS OF VWF AND FUNCTIONAL DOMAINS VWF gene in Chromosome 12

  5. ADHESION ACTIVITIES OF VWF PLATELET GPIb Collagen Heparin Sulphatide VWF:RCo A1 A2 C C C C VWF:CP VWF:CB A3 A3 SUBENDOTHELIUM COLLAGEN

  6. A.J. Reininger Single Platelets Adherent to Endothelial Monolayer

  7. A.J. Reininger Platelet Aggregate Adherent to Endothelial Monolayer

  8. MOLECULAR MARKERS of Type 3 VWD • Complete deficiency of VWF (VWF:Ag < 1) • Autosomal recessive pattern of inheritance • Rare (1- 5 per million) but severe disorder • Caused by several defects: gene deletions, • frameshift-nonsense-missense-splite site • mutations, defects of mRNA expression

  9. CLINICAL & MOLECULAR MARKERS of Type 2 VWD • Type 2A, 2B and 2M variants with decreased platelet-dependent function • Autosomal dominant • Can be caused mainly by missense mutations • (small deletions or frameshift mutations also)

  10. CLINICAL & MOLECULAR MARKERS of Type 2N VWD • Variants with markedly decreased affinity for factor VIII (FVIII) • Inherited by recessive patterns • Caused by missense mutations

  11. CLINICAL & MOLECULAR MARKERS Type 1 VWD • Inheritance (autosomal dominant) • BUT: Factors which can modify VWF levels: • Sex (females may exhibit greater variability) • Age (VWF higher in older individuals) • Exercise and stress (VWF increases) • Blood Group O (lower VWF levels)

  12. Von Willebrand disease Genetic aspect It is important to determine the causative defect of VWF gene: to prove phenotypic diagnosis or to make a definite diagnosis of VWD when the phenotypic diagnosis is uncertain, Prenatal diagnosis Direct sequencing of the VWF gene

  13. Conclusion (1) We have investigated 121 unrelated VWD patients 66 unrelated type 2 VWD patients 50 unrelated type 3 VWD B patients The moleculardefects have been found in 109 patients with a detection rate of ~ 90% Nineteen novel mutations (not previously reported, in the International VWD mutation databases).

  14. Conclusion (2) Identified mutations in VWD patientsallowed direct carrier diagnosis and prenataldiagnosis Mutation analysisisnowroutinelycarried out and isused as a first line method for carrier detection and willbeused for prenataldiagnosis. All molecularanalysisfrom the DNA extraction to sequencingweredone in ourIranianComprehensive Hemophilia Treatment Center

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