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Truncated gamma-glutamyl carboxylase in rambouillet sheep.
Vet Pathol 2006; 43(4):430-7VP

Abstract

A flock of Rambouillet sheep was examined because of increased lamb mortality due to ineffective hemostasis at parturition. Decreased activities of coagulation factors II, VII, IX, and X, and severely reduced hepatic gamma-glutamyl carboxylase activity with adequate vitamin K 2,3 epoxide reductase activity was determined.(1,)(21) Parenteral vitamin K(1) supplementation did not improve vitamin K-dependent coagulation factor activities in 3 affected lambs. Affected lamb gamma-glutamyl carboxylase deoxyribonucleic acid was sequenced, and 4 single nucleotide polymorphisms (SNPs 2-5) of the gamma-glutamyl carboxylase gene were identified. Single nucleotide polymorphism-4 results in an arginine to stop codon (UGA) substitution, which prematurely terminates the peptide at residue 686 (R686Stop). This genotype (GATT/GATT) has a strong association with the coagulopathy observed in clinically affected lambs, P < 0.001. The frequency of SNP-3 in exon 11 (R486H) within the MARC 1.1 database is high in the US sheep population overall. Gamma-glutamyl carboxylase activity in hepatic microsomes from a SNP-3 homozygous lamb lacking the SNP-4 mutation (GACC/GACC) was similar to control sheep homozygous for arginine at 486 and also lacking SNP-4 (TGCC/TGCC), indicating that the R486H does not measurably impact gamma-glutamyl carboxylase activity. The remaining two SNPs (2 and 5) are located within non-coding intron sequences. These 4 SNPs allowed for determining the genotype associated with the observed fatal coagulopathy. Screening for the premature truncation (SNP-4) based on the presence of a Bbv I restriction site in clinically normal lambs but not in the homozygous affected lambs allows for detection of the heterozygous state (GATT/GACC), because carrier animals are clinically normal.

Authors+Show Affiliations

Colorado State University, College of Veterinary Medicine and Biomedical Sciences, Department of Microbiology, Immunology, and Pathology, Fort Collins, CO, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16846984

Citation

Johnson, J S., et al. "Truncated Gamma-glutamyl Carboxylase in Rambouillet Sheep." Veterinary Pathology, vol. 43, no. 4, 2006, pp. 430-7.
Johnson JS, Laegreid WS, Basaraba RJ, et al. Truncated gamma-glutamyl carboxylase in rambouillet sheep. Vet Pathol. 2006;43(4):430-7.
Johnson, J. S., Laegreid, W. S., Basaraba, R. J., & Baker, D. C. (2006). Truncated gamma-glutamyl carboxylase in rambouillet sheep. Veterinary Pathology, 43(4), pp. 430-7.
Johnson JS, et al. Truncated Gamma-glutamyl Carboxylase in Rambouillet Sheep. Vet Pathol. 2006;43(4):430-7. PubMed PMID: 16846984.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Truncated gamma-glutamyl carboxylase in rambouillet sheep. AU - Johnson,J S, AU - Laegreid,W S, AU - Basaraba,R J, AU - Baker,D C, PY - 2006/7/19/pubmed PY - 2006/9/20/medline PY - 2006/7/19/entrez SP - 430 EP - 7 JF - Veterinary pathology JO - Vet. Pathol. VL - 43 IS - 4 N2 - A flock of Rambouillet sheep was examined because of increased lamb mortality due to ineffective hemostasis at parturition. Decreased activities of coagulation factors II, VII, IX, and X, and severely reduced hepatic gamma-glutamyl carboxylase activity with adequate vitamin K 2,3 epoxide reductase activity was determined.(1,)(21) Parenteral vitamin K(1) supplementation did not improve vitamin K-dependent coagulation factor activities in 3 affected lambs. Affected lamb gamma-glutamyl carboxylase deoxyribonucleic acid was sequenced, and 4 single nucleotide polymorphisms (SNPs 2-5) of the gamma-glutamyl carboxylase gene were identified. Single nucleotide polymorphism-4 results in an arginine to stop codon (UGA) substitution, which prematurely terminates the peptide at residue 686 (R686Stop). This genotype (GATT/GATT) has a strong association with the coagulopathy observed in clinically affected lambs, P < 0.001. The frequency of SNP-3 in exon 11 (R486H) within the MARC 1.1 database is high in the US sheep population overall. Gamma-glutamyl carboxylase activity in hepatic microsomes from a SNP-3 homozygous lamb lacking the SNP-4 mutation (GACC/GACC) was similar to control sheep homozygous for arginine at 486 and also lacking SNP-4 (TGCC/TGCC), indicating that the R486H does not measurably impact gamma-glutamyl carboxylase activity. The remaining two SNPs (2 and 5) are located within non-coding intron sequences. These 4 SNPs allowed for determining the genotype associated with the observed fatal coagulopathy. Screening for the premature truncation (SNP-4) based on the presence of a Bbv I restriction site in clinically normal lambs but not in the homozygous affected lambs allows for detection of the heterozygous state (GATT/GACC), because carrier animals are clinically normal. SN - 0300-9858 UR - https://www.unboundmedicine.com/medline/citation/16846984/Truncated_gamma_glutamyl_carboxylase_in_rambouillet_sheep_ L2 - http://journals.sagepub.com/doi/full/10.1354/vp.43-4-430?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -