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Title: A Deletion Mutation in Bovine SLC4A2 is Associated with Osteopetrosis in Red Angus Cattle

item MEYERS, STACEY - University Of Illinois
item McDaneld, Tara
item SWIST, S - University Of Wyoming
item MARRON, B - University Of Illinois
item STEFFEN, DAVID - University Of Nebraska
item O'TOOLE, D. - University Of Wyoming
item O'CONNELL, JEFF - University Of Maryland
item BEEVER, JON - University Of Illinois
item Sonstegard, Tad
item Smith, Timothy - Tim

Submitted to: BMC Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2010
Publication Date: 6/1/2010
Citation: Meyers, S.N., McDaneld, T.G., Swist, S.L., Marron, B.M., Steffen, D.J., O'Toole, D., O'Connell, J.R., Beever, J.E., Sonstegard, T.S., Smith, T.P. 2010. A Deletion Mutation in Bovine SLC4A2 is Associated with Osteopetrosis in Red Angus Cattle. Biomed Central (BMC) Genomics. 11:337.

Interpretive Summary: Osteopetrosis is a skeletal disorder occurring in humans and other animals that is characterized by the formation of overly dense bones. This results from a deficiency in the number and/or function of cells, called osteoclasts, responsible for breaking down old bone during bone development and remodeling. Recently, a number of Red Angus cattle affected with a genetic form of the disease have been reported. To identify the mutation causing the cattle disorder, we first investigated genes implicated in human osteopetrosis, but did not find any mutations. We then searched the entire genomes of nine normal and seven affected animals for chromosomal segments common to the affected animals but different from normal animals. One such segment was identified on cattle chromosome 4. This region contains SLC4A2, a gene necessary for proper osteoclast maintenance and function. We sequenced SLC4A2 in normal and affected animals, and found that affected animals are missing a critical portion of the gene. Genetic testing based on this difference will allow Red Angus cattle producers to make informed breeding decisions and reduce the frequency of this defect. Additionally, it may now be worthwhile to investigate the role of SLC4A2 in human osteopetrosis cases of unknown cause.

Technical Abstract: Osteopetrosis is a skeletal disorder characterized by the formation of overly dense bones in affected humans and animals, resulting from a deficiency in the number and/or function of bone-resorbing osteoclast cells. In cattle, osteopetrosis can either be induced during gestation by viral infection of the dam, or inherited as a recessive defect. Genetically affected cattle are typically aborted late in gestation, display skull deformities and exhibit a marked reduction of osteoclasts. Although mutations in several genes are associated with osteopetrosis in humans and mice, the genetic basis of the cattle disorder was previously unknown. We have conducted a whole-genome association analysis to identify the mutation responsible for inherited osteopetrosis in Red Angus cattle. Analysis of >54,000 SNP genotypes for each of seven affected calves and nine control animals localized the defective gene to the telomeric end of bovine chromosome 4 (BTA4). Homozygosity analysis refined the interval to a 3.4-Mb region containing the SLC4A2 gene, encoding an anion exchanger protein necessary for proper osteoclast function. Examination of SLC4A2 from normal and affected animals revealed a ~2.8-kb deletion mutation in the affected calves that encompasses exon 2 and nearly half of exon 3. Analysis of transcripts from a confirmed heterozygous individual revealed normal transcripts as well as transcripts lacking exons 2 and 3. Genotyping of additional animals demonstrated complete concordance of the homozygous deletion genotype with the osteopetrosis phenotype. Histological examination of affected tissues revealed scarce, morphologically abnormal osteoclasts displaying evidence of apoptosis. These results indicate that a deletion mutation within bovine SLC4A2 is associated with osteopetrosis in Red Angus cattle. Removal of the sequence containing the start codon within exon 2 likely precludes SLC4A2 protein expression. Loss of SLC4A2 should result in cytoplasmic alkalinization of osteoclasts which, in turn, may disrupt acidification of resorption lacunae and likely induces premature cell death.