+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins



A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins



British Journal of Haematology 103(4): 1051-1060



A variety of mutations are found in haemophilia A families. Those with circulating, dysfunctional protein can provide insights into structural determinants of factor VIII function. A molecular model based upon the crystal structure of the homologous A domains in caeruloplasmin enables predictions of molecular consequences of mutations. To identify haemophilic mutations in coding regions for three A domains of factor VIII and predict amino acid substitutions important for coagulant cofactor function, amplified DNA fragments from 188 unrelated haemophilia A families were screened for heteroduplex formation. Exons 1-19 were examined. 65 families were positive for 58 distinct mutations (39 novel) on DNA sequencing. 12 were non-missense mutations. 38 missense mutations were found in patients that circulate or potentially circulate dysfunctional factor VIII protein and are in an A domain molecular model. Of these 38, 12 have identical residues among all known species of factors V, VIII and caeruloplasmin. These 38 mutations have been localized onto a factor VIII A domain molecular model. Of these, 19 are in coiled, 15 in beta-pleated sheet, and two each in turns and alpha-helical structures. 15 substituted residues are on the surface, nine are partially on the surface and 14 are buried within the model structure. Mutant side-chain substitutions were inserted to predict changes in surface groups or, for buried residues, potential surface areas whose structure is probably disrupted by the substitution.

Please choose payment method:






(PDF emailed within 1 workday: $29.90)

Accession: 045057921

Download citation: RISBibTeXText

PMID: 9886318


Related references

Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions. Haemophilia 11(5): 481-491, 2005

Factor VIII mutations in 42 Moldovan haemophilia A families, including 12 that are novel. Haemophilia 15(4): 942-951, 2009

Ten novel factor VIII (F8C) mutations in eighteen haemophilia A families detected in Singapore. Haemophilia 16(3): 551-553, 2010

Factor VIII inhibitors in two families with mild haemophilia A: structural analysis of the mutations. Haemostasis 30(5): 268-279, 2001

Factor Viii Inhibitors in Two Families with Mild Haemophilia A: Structural Analysis of the Mutations. Pathophysiology of Haemostasis and Thrombosis 30(5): 268-279, 2000

Identification of intron 1 and 22 inversion mutations in the factor VIII gene of 124 Iranian families with severe haemophilia A. Haemophilia 10(4): 410-411, 2004

Analysis of factor VIII gene inversion mutations in 166 unrelated haemophilia A families: frequency and utility in genetic counselling. Haemophilia 2(1): 18-23, 1996

Analysis of Bcl I polymorphism of factor VIII gene in the molecular diagnosis of female haemophilia A carriers in northwestern Venezuelan families. Sangre 44(1): 19-23, 1999

Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954-->Leu substitution in the factor VIII A3 domain. British Journal of Haematology 105(4): 1123-1126, 1999

Diagnostic importance of the two-stage factor VIII:C assay demonstrated by a case of mild haemophilia associated with His1954 fwdarw Leu substitution in the factor VIII A3 domain. British Journal of Haematology 105(4): 1123-1126, 1999

The incidence of factor VIII inhibitors in severe haemophilia A following a major switch from full-length to B-domain-deleted factor VIII: a prospective cohort comparison. Haemophilia 21(2): 219-226, 2015

Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene. Haemophilia 13(3): 311-316, 2007

A novel cause of mild/moderate hemophilia A: mutations scattered in the factor VIII C1 domain reduce factor VIII binding to von Willebrand factor. Blood 96(3): 958-965, 2000

Determinants of the factor IX mutational spectrum in haemophilia B: An analysis of missense mutations using a multi-domain molecular model of the activated protein. Human Genetics 94(6): 594-608, 1994

A Single Mutation Arg2150His Regulates the T Cell Specificity for the Factor VIII C1 Domain A Molecular Mechanism Responsible for the Higher Incidence of Inhibitors in Mild/Moderate Hemophilia A Patients with Mutations in the C1 Domain. Blood 100(11): Abstract No 63, 2002