IDENTIFICATION OF THE MUTATION RESPONSIBLE FOR FACTOR XI DEFICIENCY IN HOLSTEIN CATTLE

Department of Animal Sciences, University of Illinois, Urbana, IL USA 61801

Factor XI is a serine protease involved in the early stages of the intrinsic blood coagulation pathway. An autosomal recessive deficiency of this clotting factor has been described in Holstein cattle. Cattle homozygous for the mutation suffer hemophilia-like bleeding tendencies either spontaneously or following trauma and surgical procedures. Unfortunately, current testing methods are unsuitable for accurately identifying carriers of the disease. To identify the molecular basis of this deficiency a PCR-based strategy was implemented to clone and sequence bovine FXI from both normal and deficient animals. Approximately 9.0 kb of genomic DNA sequence and 1.8 kb of cDNA sequence corresponding to exons 3 through the 3' UTR of the bovine gene were obtained. Comparison of the normal and deficient sequences showed that FXI deficiency in Holsteins is due to insertion of a 76 bp segment [GAAATAATAATTCAATAA(A)₂₆TAAAG(A)₂₇] within exon 12. This insertion introduces a stop codon that results in a mature protein lacking the functional protease domain encoded by exons 13, 14 and 15. Based on this data, a diagnostic test is being developed for genotyping. The ability to accurately genotype animals for this mutation will enable us to determine frequency and the potential impact of this disorder on the dairy industry. Additionally, we have reassigned the gene for bovine FXI to chromosome 27 using a bovine somatic cell panel.