A COL11A2 Mutation in Labrador Retrievers with Mild Disproportionate Dwarfism

Frischknecht, Mirjam; Niehof-Oellers, Helena; Jagannathan, Vidhya; Owczarek‐Lipska, Marta; Drögemüller, Cord; Dietschi, Elisabeth; Dolf, G.; Tellhelm, Bernd; Lang, Johann; Tiira, Katriina; Lohi, Hannes; Leeb, Tosso

doi:10.1371/journal.pone.0060149

Cited by 39 publications

(39 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, mice with a deficiency in collagen IX, another key component of collagen fibrils in the cartilage ECM, have abnormal skeletal properties . Lastly, Col11a2 mutations lead to mild dwarfism in Labrador retrievers . Consistent with these previous findings, cho/+ mice had thinner and less dense cortical bone compared to WT littermates.…”

Section: Discussionsupporting

confidence: 74%

Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

Holyoak

Otero

Armar

et al. 2017

Journal Orthopaedic Research

View full text Add to dashboard Cite

Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5 N) and high (9.0 N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:711-720, 2018.

show abstract

Section: Discussionsupporting

confidence: 74%

Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

Holyoak

Otero

Armar

et al. 2017

Journal Orthopaedic Research

View full text Add to dashboard Cite

show abstract

“…For instance, a GWAS of 5 cases and 8 controls sufficed to localize the gene for episodic falling syndrome in Cavalier King Charles Spaniels . Another GWAS of 23 cases and 37 controls effectively mapped the gene for disproportionate dwarfism in Labrador retrievers . According to a study of modeling in dogs, the power of our GWAS to detect a locus with dominant inheritance was at least 99%, whereas the power to detect a locus that multiplies the relative risk of the phenotype 5‐fold was 97%.…”

Section: Discussionmentioning

confidence: 97%

Paroxysmal Dyskinesia in Border Terriers: Clinical, Epidemiological, and Genetic Investigations

Stassen

Koskinen

Steenbeek

et al. 2017

Veterinary Internal Medicne

View full text Add to dashboard Cite

BackgroundIn the last decade, a disorder characterized by episodes of involuntary movements and dystonia has been recognized in Border Terriers.ObjectivesTo define clinical features of paroxysmal dyskinesia (PD) in a large number of Border Terriers and to study the genetics of the disease.Animals110 affected and 128 unaffected client‐owned Border Terriers.MethodsA questionnaire regarding clinical characteristics of PD was designed at Utrecht University and the University of Helsinki. Thirty‐five affected Border Terriers underwent physical examination and blood testing (hematology and clinical biochemistry). Diagnostic imaging of the brain was performed in 17 affected dogs and electroencephalograms (EEG) between episodes were obtained in 10 affected dogs. A genomewide association study (GWAS) was performed with DNA of 110 affected and 128 unaffected dogs.ResultsOne hundred forty‐seven questionnaires were included in the study. The most characteristic signs during episodes were dystonia, muscle fasciculations, and falling over. The majority of owners believed that their dogs remained conscious during the episodes. A beneficial effect of anti‐epileptic therapy was observed in 29 of 43 dogs. Fifteen owners changed their dogs’ diet to a hypoallergenic, gluten‐free diet, and all reported reasonable to good improvement of signs. Clinical examinations and diagnostic test results were unremarkable. The GWAS did not identify significantly associated chromosome regions.Conclusions and Clinical ImportanceThe survey results and EEG studies provided further evidence that the observed syndrome is a PD rather than epilepsy. Failure to achieve conclusive results by GWAS indicates that inheritance of PD in Border Terriers probably is complex.

show abstract

“…However, it works against fine-mapping efforts, as many marker alleles cosegregate with the causal variant. Fortunately, as the costs of conducting whole-genome sequencing (WGS) decrease, platform performance improves, and the tools needed to reliably call variants are refined, fine mapping to identify the causal genetic underpinnings of traits and diseases is becoming less laborious (Frischknecht et al 2013, Karlsson et al 2013, Owczarek-Lipska et al 2013a, Schoenebeck et al 2012). …”

Section: Genetic Approaches To Mapping Canine Traits and Diseasesmentioning

confidence: 99%

Insights into Morphology and Disease from the Dog Genome Project

Schoenebeck

Ostrander

2014

Annu. Rev. Cell Dev. Biol.

View full text Add to dashboard Cite

Although most modern dog breeds are less than 200 years old, the symbiosis between man and dog is ancient. Since prehistoric times, repeated selection events have transformed the wolf into man’s guardians, laborers, athletes, and companions. The rapid transformation from pack predator to loyal companion is a feat that is arguably unique among domesticated animals. How this transformation came to pass remained a biological mystery until recently: Within the past decade, the deployment of genomic approaches to study population structure, detect signatures of selection, and identify genetic variants that underlie canine phenotypes is ushering into focus novel biological mechanisms that make dogs remarkable. Ironically, the very practices responsible for breed formation also spurned morbidity; today, many diseases are correlated with breed identity. In this review, we discuss man’s best friend in the context of a genetic model to understand paradigms of heritable phenotypes, both desirable and disadvantageous.

show abstract

A COL11A2 Mutation in Labrador Retrievers with Mild Disproportionate Dwarfism

Cited by 39 publications

References 34 publications

Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

Collagen XI mutation lowers susceptibility to load‐induced cartilage damage in mice

Paroxysmal Dyskinesia in Border Terriers: Clinical, Epidemiological, and Genetic Investigations

Insights into Morphology and Disease from the Dog Genome Project

Contact Info

Product

Resources

About