A disease of young Holstein calves characterized by recurrent pneumonia, ulcerative and granulomatous stomatitis, enteritis with bacterial overgrowth, periodontitis, delayed wound healing, persistent neutrophilia and death at an early age had been originally described in 1983 and again in 1987. Most of these calves had stunted growth and a persistent, progressive neutrophilia (often exceeding 100,000/|jl). By investigation of pedigrees, all of the affected calves have now been traced to a common sire. Neutrophils from these calves have several functional deficits and, most importantly, fail to adhere in a fc-integrin dependent manner. The fo-integrins represent a family of glycoproteins which participate in various leukocyte adhesion reactions during host defense. The presence or absence of fc-integrin molecules can be demonstrated on the surface of neutrophils, monocytes and lymphocytes from normal or affected calves using specific monoclonal antibodies and flow cytometry, or by colloidal gold immunolabeling and scanning electron microscopy in backscatter mode. Deficiency of the fo-integrins in Holstein calves is analogous to leukocyte adhesion deficiency (LAD) seen in humans. Neutrophils in bovine (BLAD) and human LAD patients are unable to adhere to the endothelial lining of the cardiovascular system thus interrupting egression of neutrophils into infected tissues. Both BLAD cattle and LAD children (who do not receive bone marrow transplants) often die at an early age as a result of the failure of neutrophils to extravasate into infected tissues. In 1991, Shuster identified two point mutations within the alleles encoding bovine CD 18 in a Holstein calf afflicted with leukocyte adhesion deficiency. One mutation causes an aspartic acid to glycine substitution at amino acid 128 (D128G) in an extracellular region of this adhesion glycoprotein that is highly conserved (>95% identity) between humans, cattle and mice. The other mutation is silent Numerous calves with clinical symptoms of leukocyte adhesion deficiency have since been tested and all have been found homozygous for the D128G allele. In addition, calves homozygous for the D128G allele have been identified during widespread DNA testing in the United States. All cattle with the mutant allele are related to one bull, who through artificial insemination (A.I.), sired many calves in the 1950's and 1960’s. The carrier frequency of the D128G CD18 allele among U.S. Holstein cattle had reached approximately 15% among active A.I. bulls and 8% among cows. The organization of the dairy industry and the diagnostic test developed to genotype cattle, has enabled nearly complete eradication of bovine leukocyte adhesion deficiency among future A.I. bulls.
Proceedings of the World Congress on Genetics Applied to Livestock Production, Volume 21. Gene mapping; polymorphisms; disease genetic markers; marker assisted selection; gene expression; transgenes; non-convention, , 157–164, 1994
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