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Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog
Author(s) -
Christopherson Pete W.,
Bacek Lenore M.,
King Kevin B.,
Boudreaux Mary K.
Publication year - 2014
Publication title -
veterinary clinical pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.537
H-Index - 51
eISSN - 1939-165X
pISSN - 0275-6382
DOI - 10.1111/vcp.12172
Subject(s) - exon , missense mutation , genetics , mutation , point mutation , factor ix , microbiology and biotechnology , factor v , biology , gene , cytosine , medicine , thrombosis
Background Hemophilia A is an X‐linked disorder caused by a deficiency in coagulation factor VIII . Over 2300 unique mutations in the gene‐encoding factor VIII have been documented in people, but limited information is known in dogs. An 11‐week‐old male Boxer and a 5‐year‐old male German Shepherd were diagnosed with hemophilia A based on diminished factor VIII activity. Objective The purpose of the study was to identify genetic mutations associated with hemophilia A in both dogs. Methods Genomic DNA was isolated from EDTA blood samples from the affected German Shepherd and Boxer, the Boxer's dam, 3 female siblings, and one asymptomatic male sibling. Primers were designed in noncoding regions to amplify the 26 exons of the factor VIII gene via PCR . Results The affected Boxer sequence revealed a single nucleotide change, cytosine to guanine, at nucleotide position 1412 (1412C>G) in exon 10. The change is predicted to result in the substitution of arginine for proline at amino acid 471 (P471R) in the A2 domain of factor VIII . The dam and female siblings were carriers, the male sibling did not have the mutation. The German Shepherd dog had a single nucleotide change of a guanine to adenine at position 1643 (1643G>A) in exon 11, predicting the substitution of tyrosine for cysteine at amino acid 548 (C548Y) in the A2 domain. Conclusions Here we document 2 mutations associated with canine hemophilia A associated with < 1% factor VIII activity, similar to that in people. Another related Boxer with the P471R mutation was later identified.