molecular genetics in the von willebrand disease ghasem rastegarlari
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Molecular Genetics in the Von Willebrand disease
Ghasem Rastegarlari
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VON WILLEBRAND DISEASEVWD 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
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Von Willebrand diseaseGenetic aspect
Human VWF Gene
178 kb, 52 exonsmRNA 8.7 kb
VWF(12p13.3)
q
p
Chromosome 121 7 14 52
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VWF gene in Chromosome 12
5’ 3’3728167
bp 0 1000 2000 3000 4000 5000 6000 7000 8000 9000
B1B2
B3
D1 D2 D’ D3 A1 A2 A3 D4 C1 C2 COOHH2N
RGD
IIb3
FVIII Platelets Endothelial cells
CK
MultimersS-S
DimersS-S1-23 163 2813
ENCODING REGIONS OF VWFAND FUNCTIONAL DOMAINS
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PLATELETGPIb
A1
C C C CA2
A3
SUBENDOTHELIUM COLLAGEN
ADHESION ACTIVITIES OF VWF
CollagenHeparinSulphatide
VWF:RCo
VWF:CBA3
VWF:CP
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Single Platelets Adherent to Endothelial Monolayer
A.J. Reininger
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Platelet Aggregate Adherent to Endothelial Monolayer
A.J. Reininger
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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
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• 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)
CLINICAL & MOLECULAR MARKERS of Type 2 VWD
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CLINICAL & MOLECULAR MARKERS of Type 2N VWD
• Variants with markedly decreased affinity for factor VIII (FVIII)
• Inherited by recessive patterns
•Caused by missense mutations
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• 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)
CLINICAL & MOLECULAR MARKERS Type 1 VWD
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Von Willebrand diseaseGenetic 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
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Conclusion (1) We have investigated 121 unrelated VWD patients
66 unrelated type 2 VWD patients
50 unrelated type 3 VWD B patients
The molecular defects have been found in 109 patients with a
detection rate of ~ 90%
Nineteen novel mutations (not previously reported, in the International VWD mutation databases).
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Identified mutations in VWD patients allowed direct carrier diagnosis and prenatal diagnosis
Mutation analysis is now routinely carried out and is used as a first line method for carrier detection and will be used for prenatal diagnosis.
All molecular analysis from the DNA extraction to sequencing were done in our Iranian Comprehensive Hemophilia Treatment Center
Conclusion (2)