Detection of the nt230[del4] MDR1 mutation in dogs by a fluorogenic 5′ nuclease TaqMan allelic discrimination method

Klintzsch, Stefanie; Meerkamp, Kerstin; Döring, Barbara; Geyer, Joachim

doi:10.1016/j.tvjl.2009.07.018

Cited by 17 publications

(20 citation statements)

References 24 publications

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“…The nt230(del4) MDR1 mutation has to date been detected in diverse dog breeds, including Rough Collies and other related sheepdogs, such as Australian Shepherds, miniature Australian Shepherds, Border Collies, Shetland Sheepdogs, Old English Sheepdogs, English Shepherd, German Shepherd, White Swiss Shepherd, McNab as well as Wäller and two sighthounds, Longhaired Whippet and Silken Windhound. From a genealogy perspective, all of the above breeds share a common ancestor that lived in Great Britain before the breeds were classified and registered in 1873 [ 15 , 25 ]. This notion is consistent with genomic data that cluster these breeds in common clusters or sometimes even fail to differentiate between close varieties that may have undergone recent selection based on size, such as in the case of Rough Collies and Shetland Sheepdogs [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…A fast and simple detection method using allele-specific loop-mediated isothermal amplification (AS-LAMP) [ 28 ] as well as PCR-based diagnostic tests [ 29 , 30 ] and the TaqMan allelic discrimination assay [ 15 ] were designed as a result of the high clinical importance of nt230(del4) MDR1 mutation detection. Efforts to map allele frequencies in affected pure breed dogs, some of their crosses, and unrelated purebred dogs have been made in different parts of the world [ 19 , 25 , 31 – 40 ].…”

Section: Introductionmentioning

confidence: 99%

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Frequency of canine nt230(del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel - insights from a worldwide comparative perspective.

Dekel

Machluf²,

Stoler³

et al. 2017

BMC Vet Res

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BackgroundSensitivity to macrocyclic lactones, which are commonly used in veterinary clinics, was first found in Rough Collies, and was attributed in 2001 to a 4 bp deletion in the MDR1 gene. The list of affected breeds currently includes 13 breeds. Researchers from different countries and continents examined the allelic frequencies of the nt230(del4) MDR1 mutation, emphasizing the clinical importance of this test not only to mutation-prone dogs, but also to their crosses and mongrels, since treatment of a deletion carrier with these compounds may lead to its death.In this study, the allelic frequencies of nt230(del4) MDR1 mutation in affected breeds, their crosses, unrelated pure breeds and mongrels are reported for the state of Israel (n = 1416 dogs). The Israeli data were compared with reports from the US, Europe, UK, Australia and Japan.ResultsThe allelic frequencies of nt230(del4) MDR1 mutation in Israel for Australian, Swiss and German Shepherds (31%, 17% and 2.4%, respectively) are similar to the corresponding frequencies worldwide, much higher for Border Collies (4.8%), twice lower for Rough Collies (28%, compared to 55% or more elsewhere), and ~1% for mongrels. The frequencies for crosses of Australian Shepherd and Border Collies in Israel are 4 and 1.6 times lower, respectively, compared to the frequencies for the respective pure breeds.ConclusionsThis work, that for the first time presents the frequency of nt230(del4) MDR1 mutation in Israel, along with a worldwide survey, has implications for clinicians, owners and breeders of sheepdogs and their crosses and supports the need for extra care in treatment and in future breeding. Of note, the relative proportion of affected breeds, in the overall tested dogs, might be higher than their actual proportion in Israel due to directed samples collection by veterinarians for clinical purposes, as these are mainly limited to certain affected breeds or dogs that resemble them.Electronic supplementary materialThe online version of this article (10.1186/s12917-017-1251-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Frequency of canine nt230(del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel - insights from a worldwide comparative perspective.

Dekel

Machluf²,

Stoler³

et al. 2017

BMC Vet Res

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“…Compared to the conventional polymerase chain reaction (PCR) method, ME more clearly and rapidly separated the 60-bp (wild-type) and 56-bp (mutant allele) bands resulting in the clear discrimination of the three genotypes MDR1 (+/+), MDR1 (+/−), and MDR1 (−/−). This method also represents a useful tool for human genotyping studies, since at least three single nucleotides polymorphisms (SNPs) were found in the human MDR1 gene [95], which may be related to abnormal sensitivity to multiple drugs. The same year, Poe and colleagues developed a ME method employing a tetraprimer amplification refractory mutation system for the determination of the three biallelic SNPs-CYP2C9*2, CYP2C9*3, and VKORC1 haplotypes A and B-affecting clinical efficacy and toxicity of the oral anticoagulant drug warfarin [96].…”

Section: Me For Biomarker Detection In Personalized Therapy and Precimentioning

confidence: 99%

Microfluidics as a Novel Tool for Biological and Toxicological Assays in Drug Discovery Processes: Focus on Microchip Electrophoresis

et al. 2020

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The last decades of biological, toxicological, and pharmacological research have deeply changed the way researchers select the most appropriate ‘pre-clinical model’. The absence of relevant animal models for many human diseases, as well as the inaccurate prognosis coming from ‘conventional’ pre-clinical models, are among the major reasons of the failures observed in clinical trials. This evidence has pushed several research groups to move more often from a classic cellular or animal modeling approach to an alternative and broader vision that includes the involvement of microfluidic-based technologies. The use of microfluidic devices offers several benefits including fast analysis times, high sensitivity and reproducibility, the ability to quantitate multiple chemical species, and the simulation of cellular response mimicking the closest human in vivo milieu. Therefore, they represent a useful way to study drug–organ interactions and related safety and toxicity, and to model organ development and various pathologies ‘in a dish’. The present review will address the applicability of microfluidic-based technologies in different systems (2D and 3D). We will focus our attention on applications of microchip electrophoresis (ME) to biological and toxicological studies as well as in drug discovery and development processes. These include high-throughput single-cell gene expression profiling, simultaneous determination of antioxidants and reactive oxygen and nitrogen species, DNA analysis, and sensitive determination of neurotransmitters in biological fluids. We will discuss new data obtained by ME coupled to laser-induced fluorescence (ME-LIF) and electrochemical detection (ME-EC) regarding the production and degradation of nitric oxide, a fundamental signaling molecule regulating virtually every critical cellular function. Finally, the integration of microfluidics with recent innovative technologies—such as organoids, organ-on-chip, and 3D printing—for the design of new in vitro experimental devices will be presented with a specific attention to drug development applications. This ‘composite’ review highlights the potential impact of 2D and 3D microfluidic systems as a fast, inexpensive, and highly sensitive tool for high-throughput drug screening and preclinical toxicological studies.

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“…Most of them use PCR amplification of the nt230 flanking region on exon 4 of the canine MDR1 gene, followed by length polymorphism analysis using polyacrylamide gel electrophoresis [57-61]. More recently, a fluorogenic 5' nuclease TaqMan allelic discrimination method was described which allows MDR1 genotyping without post-PCR processing and is useful for routine diagnostics [62]. To date, MDR1 genotyping is also commercially available in many countries so that veterinarians can find the MDR1 genotype in a canine patient before treatment is started with a P-gp transported drug.…”

Section: Ivermectin-sensitive Collies and The Nt230(del4) Mdr1 Mutationmentioning

confidence: 99%

Treatment of MDR1 Mutant Dogs with Macrocyclic Lactones

Geyer

Janko²

2012

CPB

Self Cite

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P-glycoprotein, encoded by the multidrug resistance gene MDR1, is an ATP-driven drug efflux pump which is highly expressed at the blood-brain barrier of vertebrates. Drug efflux of macrocyclic lactones by P-glycoprotein is highly relevant for the therapeutic safety of macrocyclic lactones, as thereby GABA-gated chloride channels, which are confined to the central nervous system in vertebrates, are protected from high drug concentrations that otherwise would induce neurological toxicity. A 4-bp deletion mutation exists in the MDR1 gene of many dog breeds such as the Collie and the Australian Shepherd, which results in the expression of a non-functional P-glycoprotein and is associated with multiple drug sensitivity. Accordingly, dogs with homozygous MDR1 mutation are in general prone to neurotoxicity by macrocyclic lactones due to their increased brain penetration. Nevertheless, treatment of these dogs with macrocyclic lactones does not inevitably result in neurological symptoms, since, the safety of treatment highly depends on the treatment indication, dosage, route of application, and the individual compound used as outlined in this review. Whereas all available macrocyclic lactones can safely be administered to MDR1 mutant dogs at doses usually used for heartworm prevention, these dogs will experience neurological toxicity following a high dose regimen which is common for mange treatment in dogs. Here, we review and discuss the neurotoxicological potential of different macrocyclic lactones as well as their treatment options in MDR1 mutant dogs.

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Detection of the nt230[del4] MDR1 mutation in dogs by a fluorogenic 5′ nuclease TaqMan allelic discrimination method

Cited by 17 publications

References 24 publications

Frequency of canine nt230(del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel - insights from a worldwide comparative perspective.

Frequency of canine nt230(del4) MDR1 mutation in prone pure breeds, their crosses and mongrels in Israel - insights from a worldwide comparative perspective.

Microfluidics as a Novel Tool for Biological and Toxicological Assays in Drug Discovery Processes: Focus on Microchip Electrophoresis

Treatment of MDR1 Mutant Dogs with Macrocyclic Lactones

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