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, n=85Type 3 VWD, n=85Type 3 VWD, n=85Type 3 VWD, n=85

• Mutations throughout VWF

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 n.j.beauchamp@shef.ac.uk

• Complete form at this meeting, pass to Anne Goodeve/ post / Fax to Sheffield

AcknowledgementsAcknowledgementsAcknowledgementsAcknowledgements

• Aventis• David Lillicrap• Ross MacLachlan• Nick Beauchamp - database manager