<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:10.1073/pnas.1709082114

Cited by 99 publications

(163 citation statements)

References 51 publications

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“…To find the causative variant, several steps of filtration were applied based on the incidence of the disease, expected mode of inheritance, and functional annotation of the genomic variants. To exclude common variants in dogs, a control database of common genomic variants found in 100 dogs including 2 Boston Terriers with minor allele frequency >1% was used 33,34 . Only 150,668 variants were found to be unique to the affected dog.…”

Section: Resultsmentioning

confidence: 99%

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Mansour

Woolard

Vernau

et al. 2020

Sci Rep

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Mucopolysaccharidosis (MPS) is a metabolic storage disorder caused by the deficiency of any lysosomal enzyme required for the breakdown of glycosaminoglycans. A 15-month-old Boston Terrier presented with clinical signs consistent with lysosomal storage disease including corneal opacities, multifocal central nervous system disease and progressively worsening clinical course. Diagnosis was confirmed at necropsy based on histopathologic evaluation of multiple organs demonstrating accumulation of mucopolysaccharides. Whole genome sequencing was used to uncover a frame-shift insertion affecting the alpha-L-iduronidase (IDUA) gene (c.19_20insCGGCCCCC), a mutation confirmed in another Boston Terrier presented 2 years later with a similar clinical picture. Both dogs were homozygous for the IDUA mutation and shared coat colors not recognized as normal for the breed by the American Kennel Club. In contrast, the mutation was not detected in 120 unrelated Boston Terriers as well as 202 dogs from other breeds. Recent inbreeding to select for recessive and unusual coat colors may have concentrated this relatively rare allele in the breed. The identification of the variant enables ante-mortem diagnosis of similar cases and selective breeding to avoid the spread of this disease in the breed. Boston Terriers carrying this variant represent a promising model for MpS i with neurological abnormalities in humans.Mucopolysaccharidosis (MPS) is a type of lysosomal storage disease caused by a deficiency of enzymes integral to the breakdown of glycosaminoglycans (GAGs). This serious condition, described in many species including humans and dogs, leads to the accumulation of metabolites of the GAG degradation pathway within lysosomes along with increased urinary excretion of these metabolites 1 . There are 11 known enzymes that regulate the catabolism of four different GAGs. The GAGs affected in each variant of MPS are dependent upon which enzyme is deficient 2 .In people, MPS is a chronic disease with a progressive course. Neurological abnormalities are a major component of the disease. The progressive cerebral disease typically occurs in MPS III and severe forms of MPS I, II, and VII but chronic hearing loss and vision impairment can occur in all types. Thickening of meninges and diffuse changes to the brain's white matter are also common 3,4 . Most MPS types, except for MPS III, are associated with skeletal abnormalities, joint disease, short stature and abnormal facies 5 . Cardiovascular dysfunctions like valvular heart disease, narrowing of coronary arteries, and eccentric hypertrophy are universal to all subtypes

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Section: Resultsmentioning

confidence: 99%

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Mansour

Woolard

Vernau

et al. 2020

Sci Rep

Self Cite

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“…Fibroblast growth factor 4 (fgf4) is strongly associated with autosomal recessive chondrodysplasia in at least 19 dog breeds including dachshund, corgi, and basset hound 39 . The FGF4 variant has also been shown to be the leading cause for intervertebral disc degeneration in the chondrodysplastic dogs 54 , thus, since the cats do not have this variant, disc disease is a less likely concern. However, poor breeding practices, such as striving for the shortest legs or longest body, could lead to similar health concerns in the cats to those that plague the dwarf dog breeds 55 .…”

Section: Genome-wide Associationmentioning

confidence: 99%

Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia

Lyons

Fox

Chesney

et al. 2019

Preprint

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Despite the contribution of a few major genes for disproportionate dwarfism in humans, many dwarf patients are yet genetically undiagnosed. In domestic cats, disproportionate dwarfism has led to the development of a defined breed, the Munchkin or Minuet. This study examined the genetic aspects of feline dwarfism to consider cats as a new biomedical model. DNA from dwarf cats was genetically analyzed using parentage, linkage, and genome-wide association studies as well as whole genome sequencing.Each genetic approach localized the dwarfism phenotype to a region on cat chromosome B1. No coding variants suspected as causal for the feline dwarfism were identified but a critical region of ~5.7 Mb from B1:170,278,183-175,975,857 was defined, which implicates a novel gene controlling disproportionate dwarfism. A yet unidentified but novel gene variant, likely structural or regulatory, produces disproportionate dwarfism in cats, which may define undiagnosed human patients.

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“…Inflammatory mediators ( IL1β, IL6, PTGES1 ) and canonical Wnt signaling ( AXIN2, CCND1, DKK3, FZD1, LRP5A , and WIF1 ) were also assessed. A subset of donors were assayed for the FGF4 retrogene insertion on CFA12 and 18 using a PCR‐based assay, as described by Brown et al, with some minor modifications. Details on FGF4 genotyping and RT‐qPCR methods and primers are provided in Supplementary File 1.…”

Section: Methodsmentioning

confidence: 99%

“…While it cannot be excluded that histology may even differ between CD breeds, there is evidence that the growth plates of the long bones of CD dogs show disorganization of the proliferative zone and reduction in depth of the maturation zone in comparison with non‐chondrodystrophic (NCD) dogs . Expressed fibroblast growth factor 4 ( FGF4 ) retrogenes on CFA12 or CFA18, leading to over‐activation of fibroblast growth factor receptor 3 (FGFR3), have been agreed on as the cause of chondrodystrophy in dogs . In a similar fashion, several mutations causing enhanced FGFR3 activity can lead to achondroplasia in humans .…”

mentioning

confidence: 99%

Dog as a Model for Osteoarthritis: The FGF4 Retrogene Insertion May Matter

Tellegen

Dessing

Houben

et al. 2019

Journal Orthopaedic Research

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Osteoarthritis (OA) is a degenerative joint disease associated with chronic pain and disability in humans and companion animals. The canine species can be subdivided into non‐chondrodystrophic (NCD) and chondrodystrophic (CD) dogs, the latter having disproportionally short limbs due to disturbance in endochondral ossification of long bones. This phenotype is associated with retrogene insertions of the fibroblast growth factor 4 (FGF4) gene, resulting in enhanced fibroblast growth factor receptor 3 (FGFR3) signaling. The effect on cartilage is unknown and in experimental studies with dogs, breeds are seemingly employed randomly. The aim of this study was to determine whether CD‐ and NCD‐derived cartilage differs on a structural and biochemical level, and to explore the relationship between FGF4 associated chondrodystrophy and OA. Cartilage explants from CD and NCD dogs were cultured for 21 days. Activation of canonical Wnt signaling was assessed in primary canine chondrocytes. OA and synovitis severity from an experimental OA model were compared between healthy and OA samples from CD and NCD dogs. Release of glycosaminoglycans, DNA content, and cyclooxygenase 2 (COX‐2) expression were higher in NCD cartilage explants. Healthy cartilage from NCD dogs displayed higher cartilage degeneration and synovitis scores, which was aggravated by the induction of OA. Dikkopf‐3 gene expression was higher in NCD cartilage. No differences in other Wnt pathway read outs were found. To conclude, chondrodystrophy associated with the FGF4 retrogene seems to render CD dogs less susceptible to the development of OA when compared with NCD dogs. These differences should be considered when choosing a canine model to study the pathobiology and new treatment strategies of OA. © 2019 The Authors. Journal of Orthopaedic Research ® Published by Wiley Periodicals, Inc. J Orthop Res 37:2550–2560, 2019

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FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs

Cited by 99 publications

References 51 publications

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Whole genome sequencing for mutation discovery in a single case of lysosomal storage disease (MPS type 1) in the dog

Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia

Dog as a Model for Osteoarthritis: The FGF4 Retrogene Insertion May Matter

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