Exclusion of adrenoceptor alpha 2 variants in a horse insensitive to medetomidine

Exclusion of adrenoceptor alpha 2 variants in a horse insensitive to medetomidine Background:Patients may react in different ways to drugs, and genetic factors have to be considered when observing variability in drug responses. Drugs acting as agonists for the alpha 2 adrenoceptor (formerly called α2 adrenergic receptor), such as xylazine, detomidine, medetomidine and romifidine, are regularly used for sedation, premedication and analgesia in veterinary medicine. Three genes encode for separate subtypes of alpha 2 adrenoceptors: ADRA2A, ADRA2B and ADRA2C. Alpha 2 adrenoceptors modulate the regulation of blood pressure, renal function, insulin release, cognition, memory and behaviour. Adra2a mutant mice (α2AD79N) are resistant to sedation with dexmedetomidine.Own analysis:A 9‐year old Swiss Warmblood horse was presented due to anorexia. Because the horse was highly aggressive, clinical examination was deemed possible only under general anaesthesia. Therefore, tiletamine‐zolazepam (2 mg/kg) and medetomidine (0.04 mg/kg) were administered intramuscularly by blowpipe darting. While the drug‐related side effects such as sweating, polyuria, tremor and ataxia were observed, the sedative effect remained absent. Therefore 35 min later a second dart containing tiletamine‐zolazepam (1 mg/kg) and medetomidine (0.04 mg/kg) was shot, again without noticeable sedative effects. We sequenced the genome of this horse at 28× coverage as described (study accession no. PRJEB14779, sample accession no. SAMEA104357351). We called private variants with respect to 80 genomes from other horses of different horse breeds (Table S1). This analysis yielded 26 416 private variants, 222 of them predicted to be protein‐changing (Table S2).During this analysis we recognized that ADRA2A, ADRA2B and ADRA2C contain gaps and/or are not correctly annotated in the current EquCab 2 assembly. Therefore, our automated bioinformatics pipeline for variant detection would not necessarily have detected all possible variants within these genes. Based on preliminary data from the ongoing efforts to produce an EquCab 3 assembly we designed PCR primers for the amplification of the entire ADRA2A, ADRA2B and ADRA2C genes (Table S3). We Sanger sequenced these genes from the medetomidine‐resistant horse and a control horse and deposited curated reference sequences for these three genes in the European Nucleotide Archive (accessions LT935786–LT935788). We did not detect any protein‐changing variant in the medetomidine‐resistant horse.Comments:Coding variants in ADRA2A, ADRA2B and ADRA2C can be excluded for the observed insensitivity to medetomidine in a Swiss Warmblood horse. We provide new genomic reference sequences for these three genes.AcknowledgementsWe thank Nathalie Besuchet‐Schmutz, Muriel Fragnière and Sabrina Schenk for excellent technical assistance. We thank the Next Generation Sequencing Platform of the University of Bern for performing the whole genome sequencing experiment, and the Interfaculty Bioinformatics Unit of the University of Bern for providing high performance computing infrastructure.ReferencesBelle D. J. & Singh H. (2008) Am Fam Physician 77, 1553–60.Hobo S. et al. (1995) J Vet Med Sci 57, 507–10.England G. C. W. & Clarke K. W. (1996) Br Vet J 152, 641–57.Bylund D. B. et al. (1994) Pharmacol Rev 46, 121–36.Belfer I. et al. (2005) J Hum Genet 50, 12–20.Altman J. D. et al. (1999) Mol Pharmacol 56, 154–61.Lakhlani P. P. et al. (1997) Proc Natl Acad Sci USA 94, 9950–5.Murgiano L. et al. (2016) G3 (Bethesda), 7, 1315–21. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Animal Genetics Wiley

Exclusion of adrenoceptor alpha 2 variants in a horse insensitive to medetomidine

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Wiley
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Copyright © 2018 Stichting International Foundation for Animal Genetics
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0268-9146
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1365-2052
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10.1111/age.12636
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Abstract

Background:Patients may react in different ways to drugs, and genetic factors have to be considered when observing variability in drug responses. Drugs acting as agonists for the alpha 2 adrenoceptor (formerly called α2 adrenergic receptor), such as xylazine, detomidine, medetomidine and romifidine, are regularly used for sedation, premedication and analgesia in veterinary medicine. Three genes encode for separate subtypes of alpha 2 adrenoceptors: ADRA2A, ADRA2B and ADRA2C. Alpha 2 adrenoceptors modulate the regulation of blood pressure, renal function, insulin release, cognition, memory and behaviour. Adra2a mutant mice (α2AD79N) are resistant to sedation with dexmedetomidine.Own analysis:A 9‐year old Swiss Warmblood horse was presented due to anorexia. Because the horse was highly aggressive, clinical examination was deemed possible only under general anaesthesia. Therefore, tiletamine‐zolazepam (2 mg/kg) and medetomidine (0.04 mg/kg) were administered intramuscularly by blowpipe darting. While the drug‐related side effects such as sweating, polyuria, tremor and ataxia were observed, the sedative effect remained absent. Therefore 35 min later a second dart containing tiletamine‐zolazepam (1 mg/kg) and medetomidine (0.04 mg/kg) was shot, again without noticeable sedative effects. We sequenced the genome of this horse at 28× coverage as described (study accession no. PRJEB14779, sample accession no. SAMEA104357351). We called private variants with respect to 80 genomes from other horses of different horse breeds (Table S1). This analysis yielded 26 416 private variants, 222 of them predicted to be protein‐changing (Table S2).During this analysis we recognized that ADRA2A, ADRA2B and ADRA2C contain gaps and/or are not correctly annotated in the current EquCab 2 assembly. Therefore, our automated bioinformatics pipeline for variant detection would not necessarily have detected all possible variants within these genes. Based on preliminary data from the ongoing efforts to produce an EquCab 3 assembly we designed PCR primers for the amplification of the entire ADRA2A, ADRA2B and ADRA2C genes (Table S3). We Sanger sequenced these genes from the medetomidine‐resistant horse and a control horse and deposited curated reference sequences for these three genes in the European Nucleotide Archive (accessions LT935786–LT935788). We did not detect any protein‐changing variant in the medetomidine‐resistant horse.Comments:Coding variants in ADRA2A, ADRA2B and ADRA2C can be excluded for the observed insensitivity to medetomidine in a Swiss Warmblood horse. We provide new genomic reference sequences for these three genes.AcknowledgementsWe thank Nathalie Besuchet‐Schmutz, Muriel Fragnière and Sabrina Schenk for excellent technical assistance. We thank the Next Generation Sequencing Platform of the University of Bern for performing the whole genome sequencing experiment, and the Interfaculty Bioinformatics Unit of the University of Bern for providing high performance computing infrastructure.ReferencesBelle D. J. & Singh H. (2008) Am Fam Physician 77, 1553–60.Hobo S. et al. (1995) J Vet Med Sci 57, 507–10.England G. C. W. & Clarke K. W. (1996) Br Vet J 152, 641–57.Bylund D. B. et al. (1994) Pharmacol Rev 46, 121–36.Belfer I. et al. (2005) J Hum Genet 50, 12–20.Altman J. D. et al. (1999) Mol Pharmacol 56, 154–61.Lakhlani P. P. et al. (1997) Proc Natl Acad Sci USA 94, 9950–5.Murgiano L. et al. (2016) G3 (Bethesda), 7, 1315–21.

Journal

Animal GeneticsWiley

Published: Jan 1, 2018

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