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Principal Investigator: Dr. Marjory Brooks
Contact Information: E-mail: mbb9@cornell.edu - Phone: 607-275-0622
Sponsor: Morris Animal Foundation
Grant Number: DO5CA-018
Title: Carrier Detection to Prevent Propagation of Canine Hemophilia A
Annual Direct Cost: $36,500
Project Period: 11/01/05-10/31/07
This project develops strategies for accurate canine hemophilia A carrier detection through the use of molecular diagnostic techniques and newly available canine genome sequence. Results of these studies will have direct clinical application in controlling hemophilia. Hemophilia A is a common X-linked recessive bleeding disorder found in many different breeds. Hemophilia A is caused by deficiency of coagulation Factor VIII (FVIII) and affected dogs are definitively diagnosed by specific measurement of FVIII activity. Carrier females, however, are clinically normal and often have normal FVIII values. Hemophilia is typically propagated when these carrier females are bred.
Direct and indirect methods of carrier detection will be evaluated. We will determine the prevalence of a newly described FVIII inversion mutation in a panel of 20 breed-variants of severe hemophilia A through detection of a unique mutant FVIII transcript. We will define breakpoint regions underlying this mutation by sequencing intragenic and telomeric copies of the F8A gene. The obtained sequence will be used to design primers for direct detection of the inversion mutation in genomic DNA of affected males and suspect carrier females.
Segregation analyses provide an indirect method for carrier detection regardless of mutation-type. This strategy is based on genotyping hemophiliac families for polymorphic FVIII markers. We will develop a set of microsatellite markers to genotype newly diagnosed hemophilia A pedigrees and breed-variants previously genotyped at a single FVIII marker locus. These studies aim to define an optimized set of informative marker loci, suitable for carrier detection in many different breeds.
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