Update of von Willebrand Factor Gene Update of von Willebrand Factor Gene Defects from the ISTH VWF Web SiteDefects from the ISTH VWF Web Site
Update of von Willebrand Factor Gene Update of von Willebrand Factor Gene Defects from the ISTH VWF Web SiteDefects from the ISTH VWF Web Site
Anne Goodeve and Nick Beauchamp University of Sheffield, UK
Ross MacLachlan and David Lillicrap Kingston, Canada
http://www.shef.ac.uk/vwfhttp://www.shef.ac.uk/vwfhttp://www.shef.ac.uk/vwfhttp://www.shef.ac.uk/vwf
VWD Type in 307 EntriesVWD Type in 307 EntriesVWD Type in 307 EntriesVWD Type in 307 Entries
2A
2B
1U
3
2N 2M
Type 1 VWD, n=14Type 1 VWD, n=14Type 1 VWD, n=14Type 1 VWD, n=14
• 2 small deletions (frameshift)• 1 nonsense mutation• 11 missense mutations;
– Ex 26, 28 and 52– Codons 1130-2776– C1130F; n=1– C1149R; n=1– T1156M; n=2– Y1584C; n=1
Type 2A VWD, n=71Type 2A VWD, n=71Type 2A VWD, n=71Type 2A VWD, n=71
Subtype Exon Domain Codons No. reportsIIC 12-16 D2 404-625 7
18 D’ 771fs 128 A1 1272-1383 728 A2 1503-1672 53
IID 52 CK 2773fs 1IIE 52 CK 2773-2801 2
Total 71
Common Type 2A VWD MutationsCommon Type 2A VWD MutationsCommon Type 2A VWD MutationsCommon Type 2A VWD Mutations
Amino acid change No. reports % of 71 type 2A
S1506L 8 11R1597Q 4 6R1597W 9 13G1609R 3 4Total 24 34
Type 2B VWD, n=52Type 2B VWD, n=52Type 2B VWD, n=52Type 2B VWD, n=52
• Exon 28 • Codons 1266-1461 • A1 domain• 1 insertion mutation (1304insM)• 16 different missense mutations at 10 amino acids
Common Type 2B VWD MutationsCommon Type 2B VWD MutationsCommon Type 2B VWD MutationsCommon Type 2B VWD Mutations
Amino acid change No. reports % of 52 type 2B
R1306W 10 19R1308C 6 12V1316M 9 17R1341Q 7 13Total 32 61
Type 2M; n=18Type 2M; n=18Type 2M; n=18Type 2M; n=18
• Ex 18, 27 and 28 (n=16)• D’, D3 and A1 domains• Codons 788, 1205 and 1279-1467• No common mutations reported• I1425F reported twice
Type 2N; n=37Type 2N; n=37Type 2N; n=37Type 2N; n=37
• Ex18-24 • Codons 782-1060• D’ and D3 domains• 16 different missense changes at 15 amino acids
(R816W, R816Q)
Common Type 2N VWD MutationsCommon Type 2N VWD MutationsCommon Type 2N VWD MutationsCommon Type 2N VWD Mutations
Amino acid change No. reports % of 37 type 2N
T791M 5 14R816W 4 11R854Q 12 32Total 21 57
Type 3 VWD Mutation TypeType 3 VWD Mutation TypeType 3 VWD Mutation TypeType 3 VWD Mutation Type
NonsenseMissense
Splice Small deletion
Large deletion
Insertion
R1659X, n=5 R2535X, n=4 D141N
D141Y
5/6 into C or T run
42, 23-52, all VWF x3
2435delC x6 dinucleotide from
repeat x3 all unique
““Unclassified” VWDUnclassified” VWD““Unclassified” VWDUnclassified” VWD
• 30 entries• 1 large deletion Ex 26-34• 1 deletion 3 nt (2 aa substitution) • 1 insertion 105 nt (sequence duplication)• 27 missense
““Unclassified” VWD, n=30Unclassified” VWD, n=30““Unclassified” VWD, n=30Unclassified” VWD, n=30
Exon Domain Amino acid change
No. reports
Phenotype
25-26 D3 1101-1196 7 2Q Bern in 127 D3 R1205H/L 2 Vicenza28 A1 R1374C/H/L/S 530 A1 S1371T 1 Decreased
collagen binding38 D4 L2207P 152 CK C2806R 1 Dimer defect
VWF Mutation Type in 307 EntriesVWF Mutation Type in 307 EntriesVWF Mutation Type in 307 EntriesVWF Mutation Type in 307 Entries
MissenseInsertionNonsense Small delSplice Large del
2 3-10 11-17 18-20 20-28 28 28 28-32 33-34 35-39 40-42 -44 45-48 49-52
S D1 D2 D’ D3 A1 A2 A3 D4 B1-B3 C1 C2 CK
Location of 307 VWF MutationsLocation of 307 VWF MutationsLocation of 307 VWF MutationsLocation of 307 VWF Mutations
D’-D3
21
A
54
D4-CK
11
D1-D2
12
% of 307
mutations
Large deletions 2%
• Send suggestions/comments/mutations/polymorphisms to the database manager [email protected]
• Complete form at this meeting, pass to Anne Goodeve/ post / Fax to Sheffield