<i>FGF4</i>retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs

Brown, Emily; Dickinson, Peter J.; Mansour, Tamer; Sturges, Beverly K.; Aguilar, Miriam; Young, Amy; Korff, Courtney; Lind, Jenna; Ettinger, Cassandra L.; Varon, S. L. Barrero; Pollard, Rachel E.; Brown, C. Titus; Raudsepp, Terje; Bannasch, Danika L.

doi:10.1101/144022

Cited by 10 publications

(22 citation statements)

References 61 publications

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“…5). We found that GFrelated signaling pathways were involved in the crosstalk network, mainly including the previously reported FGF family, 143,146 TGF-β family, 147,148 BMP family, 149,150 and PDGF family. 151 Among them, TGF-β was important due to the high activation of SMAD3 in NPPCs.…”

Section: Discussionmentioning

confidence: 72%

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs

Zhu

et al. 2021

Bone Res

144

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A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development, homeostasis, and disease of human intervertebral disks (IVDs) remains challenging. Here, the transcriptomic landscape of 108 108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs, including the nucleus pulposus (NP), annulus fibrosus, and cartilage endplate (CEP). The chondrocyte subclusters were classified based on their potential regulatory, homeostatic, and effector functions in extracellular matrix (ECM) homeostasis. Notably, in the NP, a PROCR+ resident progenitor population showed enriched colony-forming unit-fibroblast (CFU-F) activity and trilineage differentiation capacity. Finally, intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-β cascades are important cues in the NP microenvironment. In conclusion, a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.

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Section: Discussionmentioning

confidence: 72%

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs

Zhu

et al. 2021

Bone Res

144

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“…2d). Of the seventeen autosomal QTLs that have been previously associated with body size (5,8,14–22,25), only one (CFA3:62) did not reach significance using the imputed panel (significance threshold of P = 1×10 −8 ), with P -values of 1.1×10 −5 , 2.1×10 −7 and 1.8×10 −8 for individual weight, breed-average weight and breed-average height respectively (S2 Table). GWAS of breed-average weight provided the most power on average, so we will focus on that phenotype for the rest of the body size analyses.…”

Section: Resultsmentioning

confidence: 99%

Imputation of canine genotype array data using 365 whole-genome sequences improves power of genome-wide association studies

Hayward

White

Boyle

et al. 2019

Preprint

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Genomic resources for the domestic dog have improved with the widespread adoption of a 173k SNP array platform and updated reference genome. SNP arrays of this density are sufficient for detecting genetic associations within breeds but are underpowered for finding associations across multiple breeds or in mixed-breed dogs, where linkage disequilibrium rapidly decays between markers, even though such studies would hold particular promise for mapping complex diseases and traits. Here we introduce an imputation reference panel, consisting of 365 diverse, whole-genome sequenced dogs and wolves, which increases the number of markers that can be queried in genome-wide association studies approximately 130-fold. Using previously genotyped dogs, we show the utility of this reference panel in identifying novel associations and fine-mapping for canine body size and blood phenotypes, even when causal loci are not in strong linkage disequilibrium with any single array marker. This reference panel resource will improve future genome-wide association studies for canine complex diseases and other phenotypes.Author SummaryComplex traits are controlled by more than one gene and as such are difficult to map. For complex trait mapping in the domestic dog, researchers use the current array of 173,000 variants, with only minimal success. Here, we use a method called imputation to increase the number of variants – from 173,000 to 24 million – that can be queried in canine association studies. We use sequence data from the whole genomes of 365 dogs and wolves to accurately predict variants, in a separate cohort of dogs, that are not present on the array. Using dog body size, we show that the increase in variants results in an increase in mapping power, through the identification of new associations and the narrowing of regions of interest. This imputation panel is particularly important because of its usefulness in improving complex trait mapping in the dog, which has significant implications for discovery of variants in humans with similar diseases.

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“…It is also highly prevalent within the French Bulldog, Dachshund, Beagle and Cocker Spaniel breeds, who are all associated with intervertebral disc herniation. 15 The combination of these two genetic findings may help in part to explain the incidence of IVDH in the French Bulldog breed. 12 Specifically, the DVL2 gene through its contribution to the formation of French Bulldogs screw tail and thoracic CVM, and the possible destabilizing spinal effects this causes, in conjunction with increased rate of disc degeneration caused by the FGF4 gene.…”

Section: Discussionmentioning

confidence: 99%

“…1,9,[12][13][14] However there is also a genetic association between chondrodystrophy and accelerated disc degeneration in the French Bulldog due to the FGF4 retrogene. 15,16 The role of genetics in the development of CVM has also been investigated with genomic sequencing finding a link between the presence of screw tails and thoracic vertebral malformations in the Bulldog breeds due to a frameshift mutation in the Disheveled 2 (DVL2) gene. 17 The majority of research into the significance of CVM in these breeds is based on European populations of dogs.…”

mentioning

confidence: 99%

The presence, morphology and clinical significance of vertebral body malformations in an Australian population of French Bulldogs and Pugs

Brown¹,

Podadera

Ward

et al. 2021

Aust Veterinary J

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Objective To describe the incidence, morphology and clinical significance of congenital vertebral malformations (CVM) in two breeds of brachycephalic dogs presenting to a referral veterinary hospital.Design Prospective cohort study series.Materials and methods Forty-nine French Bulldogs and Pugs were prospectively evaluated and placed in one of two groups based on whether or not they presented for neurological signs referable to spinal cord disease. A computed tomography (CT) of their entire spine was obtained and the presence and classification of CVM along with the degree of spinal kyphosis recorded for all dogs. Statistical analysis was performed to identify clinical associations between these factors (P < 0.05).Results CVM were prevalent across both breeds with the French Bulldog having more malformations than the Pug (Kruskal-Wallis nonparametric analysis of variance, P < 0.0001). Breed associated vertebral malformation subtypes included butterfly subtype in French Bulldogs (Chi-square, P = 0.0002), and transitional subtype in Pugs (odds ratio, 22.7; P = 0.000). A new subtype, dorsal wedge, was observed in 12 cases. The presence, number and subtype of vertebral malformation were not reliable for predicting the development of neurological signs across both breeds (Chisquare, P > 0.05). However, spinal kyphosis >35 calculated via Cobb angle was associated with Pugs that had neurological deficits (Chi-square, P = 0.028).Conclusions Congenital vertebral malformations largely appear to be incidental findings in this population of French Bulldogs but are of more significance in the Pug breed when spinal kyphosis is >35 . French Bulldogs that have spinal cord disease and CVM are more likely to have pathology distant to CVM with intervertebral disc herniation most common.

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FGF4retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs

Cited by 10 publications

References 61 publications

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs

Spatially defined single-cell transcriptional profiling characterizes diverse chondrocyte subtypes and nucleus pulposus progenitors in human intervertebral discs

Imputation of canine genotype array data using 365 whole-genome sequences improves power of genome-wide association studies

The presence, morphology and clinical significance of vertebral body malformations in an Australian population of French Bulldogs and Pugs

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