Exclusion of adrenoceptor alpha 2 variants in
a horse insensitive to medetomidine
Isabelle Schmutz*, Vidhya Jagannathan*,
Sabina Diez Bernal
, Simone Lanz
, Tosso Leeb* and
*Vetsuisse Faculty, Institute of Genetics, University of Bern,
Bremgartenstrasse 109a, 3001 Bern, Switzerland;
Anaesthesiology, Department of Clinical Veterinary Medicine,
Vetsuisse Faculty, University of Bern, 3001 Bern, Switzerland;
Swiss Institute of Equine Medicine, University of Bern and
Agroscope, 3001 Bern, Switzerland;
School of Medicine,
University of Louisville, 40202 Louisville, KY, USA
Accepted for publication 29 November 2017
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 a
receptor), such as xylazine, detomidine, medetomidine and
romiﬁdine, are regularly used for sedation, premedication
and analgesia in veterinary medicine.
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 (a
D79N) are resistant to sedation
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-zolaze-
pam (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 medeto-
midine (0.04 mg/kg) was shot, again without noticeable
sedative effects. We sequenced the genome of this horse at
289 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 pre-
dicted to be protein-changing (Table S2).
During this analysis we recognized that ADRA2A,
ADRA2B and ADRA2C contain gaps and/or are not cor-
rectly annotated in the current EquCab 2 assembly.
Therefore, our automated bioinformatics pipeline for vari-
ant detection would not necessarily have detected all pos-
sible 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.
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.
We thank Nathalie Besuchet-Schmutz,
ere and Sabrina Schenk for excellent techni-
cal assistance. We thank the Next Generation Sequencing
Platform of the University of Bern for performing the
whole genome sequencing experiment, and the Interfac-
ulty Bioinformatics Unit of the University of Bern for pro-
viding high performance computing infrastructure.
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Correspondence: T. Leeb (firstname.lastname@example.org)
Additional supporting information may be found online in
the supporting information tab for this article:
Table S1 Sample designations and breed information on
81 horses with genome sequences.
Table S2 Private variants in the genome of the Swiss
Warmblood with medetomidine resistance.
Table S3 Primer sequences for the ampliﬁcation of the
equine ADRA2A, ADRA2B and ADRA2C genes.
© 2018 Stichting International Foundation for Animal Genetics, 49, 141–143