Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs
Abstract
:1. Introduction
2. Materials and Methods
2.1. Samples
2.2. Phenotyping and Genotyping
2.3. Statistical Analysis
3. Results
3.1. Allele Frequency
3.2. Description and Genotype of Disc Decompressive Surgical Cases
3.3. Linear Regression of Age at Surgery
3.4. Evaluation of Disc Calcification
3.5. Relative Risk
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
- Brown, E.A.; Dickinson, P.J.; Mansour, T.; Sturges, B.K.; Aguilar, M.; Young, A.E.; Korff, C.; Lind, J.; Ettinger, C.L.; Varon, S.; et al. FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs. Proc. Natl. Acad. Sci. USA 2017, 114, 11476–11481. [Google Scholar] [CrossRef] [PubMed]
- Parker, H.G.; VonHoldt, B.M.; Quignon, P.; Margulies, E.H.; Shao, S.; Mosher, D.S.; Spady, T.C.; Elkahloun, A.; Cargill, M.; Jones, P.G. An expressed FGF4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 2009, 325, 995–998. [Google Scholar] [CrossRef] [PubMed]
- Sutter, N.B.; Mosher, D.S.; Gray, M.M.; Ostrander, E.A. Morphometrics within dog breeds are highly reproducible and dispute Rensch’s rule. Mamm. Genome 2008, 19, 713–723. [Google Scholar] [CrossRef] [PubMed]
- Boulet, A.M.; Capecchi, M.R. Signaling by FGF4 and FGF8 is required for axial elongation of the mouse embryo. Dev. Biol. 2012, 371, 235–245. [Google Scholar] [CrossRef] [PubMed]
- Niswander, L.; Martin, G.R. Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development 1992, 114, 755–768. [Google Scholar] [PubMed]
- Lu, P.; Minowada, G.; Martin, G.R. Increasing FGF4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Development 2006, 133, 33–42. [Google Scholar] [CrossRef] [PubMed]
- Horton, W.A.; Hall, J.G.; Hecht, J.T. Achondroplasia. Lancet 2007, 370, 162–172. [Google Scholar] [CrossRef]
- Foldynova-Trantirkova, S.; Wilcox, W.R.; Krejci, P. Sixteen years and counting: The current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias. Hum. Mutat. 2012, 33, 29–41. [Google Scholar] [CrossRef]
- Smolders, L.A.; Bergknut, N.; Grinwis, G.C.; Hagman, R.; Lagerstedt, A.S.; Hazewinkel, H.A.; Tryfonidou, M.A.; Meij, B.P. Intervertebral disc degeneration in the dog. Part 2: Chondrodystrophic and non-chondrodystrophic breeds. Vet. J. 2013, 195, 292–299. [Google Scholar] [CrossRef]
- Hansen, H.-J. A pathologic-anatomical study on disc degeneration in dog: With special reference to the so-called enchondrosis intervertebralis. Acta Orthop. Scand. 1952, 23, 1–130. [Google Scholar] [CrossRef]
- Braund, K.; Ghosh, P.; Taylor, T.; Larsen, L. Morphological studies of the canine intervertebral disc. The assignment of the beagle to the achondroplastic classification. Res. Vet. Sci. 1975, 19, 167–172. [Google Scholar] [CrossRef]
- Jeffery, N.D.; Levine, J.M.; Olby, N.J.; Stein, V.M. Intervertebral disk degeneration in dogs: Consequences, diagnosis, treatment, and future directions. J. Vet. Intern. Med. 2013, 27, 1318–1333. [Google Scholar] [CrossRef] [PubMed]
- Lappalainen, A.K.; Vaittinen, E.; Junnila, J.; Laitinen-Vapaavuori, O. Intervertebral disc disease in Dachshunds radiographically screened for intervertebral disc calcifications. Acta Vet. Scand. 2014, 56, 89. [Google Scholar] [CrossRef] [PubMed]
- Jensen, V.F.; Beck, S.; Christensen, K.A.; Arnbjerg, J. Quantification of the association between intervertebral disk calcification and disk herniation in Dachshunds. J. Am. Vet. Med Assoc. 2008, 233, 1090–1095. [Google Scholar] [CrossRef] [Green Version]
- Lappalainen, A.K.; Maki, K.; Laitinen-Vapaavuori, O. Estimate of heritability and genetic trend of intervertebral disc calcification in Dachshunds in Finland. Acta Vet. Scand. 2015, 57, 78. [Google Scholar] [CrossRef] [PubMed]
- Goggin, J.E.; Li, A.S.; Franti, C.E. Canine intervertebral disk disease: Characterization by age, sex, breed, and anatomic site of involvement. Am. J. Vet. Res. 1970, 31, 1687–1692. [Google Scholar] [PubMed]
- Cherrone, K.L.; Dewey, C.W.; Coates, J.R.; Bergman, R.L. A retrospective comparison of cervical intervertebral disk disease in nonchondrodystrophic large dogs versus small dogs. J. Am. Anim. Hosp. Assoc. 2004, 40, 316–320. [Google Scholar] [CrossRef]
- Hansen, H.-J. A pathologic-anatomical interpretation of disc degeneration in dogs. Acta Orthop. Scand. 1951, 20, 280–293. [Google Scholar] [CrossRef] [PubMed]
- Hansen, T.; Smolders, L.A.; Tryfonidou, M.A.; Meij, B.P.; Vernooij, J.C.M.; Bergknut, N.; Grinwis, G.C.M. The Myth of Fibroid Degeneration in the Canine Intervertebral Disc: A Histopathological Comparison of Intervertebral Disc Degeneration in Chondrodystrophic and Nonchondrodystrophic Dogs. Vet. Pathol. 2017, 54, 945–952. [Google Scholar] [CrossRef]
- Mayhew, P.D.; McLear, R.C.; Ziemer, L.S.; Culp, W.T.; Russell, K.N.; Shofer, F.S.; Kapatkin, A.S.; Smith, G.K. Risk factors for recurrence of clinical signs associated with thoracolumbar intervertebral disk herniation in dogs: 229 cases (1994–2000). J. Am. Vet. Med. Assoc. 2004, 225, 1231–1236. [Google Scholar] [CrossRef]
- Jensen, V.F.; Christensen, K.A. Inheritance of Disc Calcification in the Dachshund. J. Vet. Med. Ser. A 2001, 47, 331–340. [Google Scholar] [CrossRef]
- Kranenburg, H.J.; Grinwis, G.C.; Bergknut, N.; Gahrmann, N.; Voorhout, G.; Hazewinkel, H.A.; Meij, B.P. Intervertebral disc disease in dogs—Part 2: Comparison of clinical, magnetic resonance imaging, and histological findings in 74 surgically treated dogs. Vet. J. 2013, 195, 164–171. [Google Scholar] [CrossRef] [PubMed]
- Bergknut, N.; Smolders, L.A.; Grinwis, G.C.; Hagman, R.; Lagerstedt, A.S.; Hazewinkel, H.A.; Tryfonidou, M.A.; Meij, B.P. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc and characteristics of intervertebral disc degeneration. Vet. J. 2013, 195, 282–291. [Google Scholar] [CrossRef] [PubMed]
- Bergknut, N.; Egenvall, A.; Hagman, R.; Gustås, P.; Hazewinkel, H.A.; Meij, B.P.; Lagerstedt, A.-S. Incidence of intervertebral disk degeneration–related diseases and associated mortality rates in dogs. J. Am. Vet. Med. Assoc. 2012, 240, 1300–1309. [Google Scholar] [CrossRef] [PubMed]
- Mayousse, V.; Desquilbet, L.; Jeandel, A.; Blot, S. Prevalence of neurological disorders in French bulldog: A retrospective study of 343 cases (2002–2016). BMC Vet. Res. 2017, 13, 212. [Google Scholar] [CrossRef] [PubMed]
- Hiyama, A.; Sakai, D.; Risbud, M.V.; Tanaka, M.; Arai, F.; Abe, K.; Mochida, J. Enhancement of intervertebral disc cell senescence by WNT/β-catenin signaling-induced matrix metalloproteinase expression. Arthritis Rheum. 2010, 62, 3036–3047. [Google Scholar] [CrossRef] [PubMed]
- Smolders, L.A.; Meij, B.P.; Onis, D.; Riemers, F.M.; Bergknut, N.; Wubbolts, R.; Grinwis, G.C.; Houweling, M.; Groot Koerkamp, M.J.; van Leenen, D.; et al. Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: Implications for development of regenerative strategies. Arthritis Res. Ther. 2013, 15, R23. [Google Scholar] [CrossRef] [PubMed]
- Dahia, C.L.; Mahoney, E.J.; Durrani, A.A.; Wylie, C. Intercellular signaling pathways active during intervertebral disc growth, differentiation, and aging. Spine 2009, 34, 456–462. [Google Scholar] [CrossRef] [PubMed]
- Mansour, T.A.; Lucot, K.; Konopelski, S.E.; Dickinson, P.J.; Sturges, B.K.; Vernau, K.L.; Choi, S.; Stern, J.A.; Thomasy, S.M.; Doring, S.; et al. Whole genome variant association across 100 dogs identifies a frame shift mutation in DISHEVELLED 2 which contributes to Robinow-like syndrome in Bulldogs and related screw tail dog breeds. PLoS Genet. 2018, 14, e1007850. [Google Scholar] [CrossRef]
- Kaessmann, H.; Vinckenbosch, N.; Long, M. RNA-based gene duplication: Mechanistic and evolutionary insights. Nat. Rev. Genet. 2009, 10, 19–31. [Google Scholar] [CrossRef]
- Carelli, F.N.; Hayakawa, T.; Go, Y.; Imai, H.; Warnefors, M.; Kaessmann, H. The life history of retrocopies illuminates the evolution of new mammalian genes. Genome Res. 2016, 26, 301–314. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Antequera, F. Structure, function and evolution of CpG island promoters. Cell. Mol. Life Sci. 2003, 60, 1647–1658. [Google Scholar] [CrossRef] [PubMed]
- Simpson, S.T. Intervertebral disc disease. Vet. Clin. N. Am. Small Anim. Pract. 1992, 22, 889–897. [Google Scholar] [CrossRef]
- Packer, R.M.; Seath, I.J.; O’Neill, D.G.; De Decker, S.; Volk, H.A. DachsLife 2015: An investigation of lifestyle associations with the risk of intervertebral disc disease in Dachshunds. Canine Genet. Epidemiol. 2016, 3, 8. [Google Scholar] [CrossRef] [PubMed]
- Mogensen, M.S.; Karlskov-Mortensen, P.; Proschowsky, H.F.; Lingaas, F.; Lappalainen, A.; Lohi, H.; Jensen, V.F.; Fredholm, M. Genome-Wide Association Study in Dachshund: Identification of a Major Locus Affecting Intervertebral Disc Calcification. J. Hered. 2011, 102, S81–S86. [Google Scholar] [CrossRef] [Green Version]
- Packer, R.M.; Hendricks, A.; Volk, H.A.; Shihab, N.K.; Burn, C.C. How long and low can you go? Effect of conformation on the risk of thoracolumbar intervertebral disc extrusion in domestic dogs. PLoS ONE 2013, 8, e69650. [Google Scholar] [CrossRef]
- Stigen, Ø.; Christensen, K. Calcification of intervertebral discs in the dachshund: An estimation of heritability. Acta Vet. Scand. 1993, 34, 357–361. [Google Scholar]
- Stigen, Ø. Calcification of intervertebral discs in the dachshund: A radiographic study of 115 dogs at 1 and 5 years of age. Acta Vet. Scand. 1996, 37, 229–237. [Google Scholar]
- Rohdin, C.; Jeserevic, J.; Viitmaa, R.; Cizinauskas, S. Prevalence of radiographic detectable intervertebral disc calcifications in Dachshunds surgically treated for disc extrusion. Acta Vet. Scand. 2010, 52, 24. [Google Scholar] [CrossRef]
- Chai, O.; Harrosh, T.; Bdolah-Avram, T.; Mazaki-Tovi, M.; Shamir, M.H. Characteristics of and risk factors for intervertebral disk extrusions in Pekingese. J. Am. Vet. Med. Assoc. 2018, 252, 846–851. [Google Scholar] [CrossRef]
- Stigen, Ø.; Kolbjørnsen, Ø. Calcification of intervertebral discs in the dachshund: A radiographic and histopathologic study of 20 dogs. Acta Vet. Scand. 2007, 49, 39. [Google Scholar] [CrossRef]
- Stigen, Ø.; Ciasca, T.; Kolbjørnsen, Ø. Calcification of extruded intervertebral discs in dachshunds: A radiographic, computed tomographic and histopathological study of 25 cases. Acta Vet. Scand. 2019, 61, 13. [Google Scholar] [CrossRef]
Breed | Retrospective Surgery Cases | Percent of Total Surgeries | Total in Repository | Surgery Prevalence in Repository | Prospective Surgery Cases | 12-FGF4RG Frequency | 18-FGF4RG Frequency | Median Age at Surgery (Years) |
---|---|---|---|---|---|---|---|---|
Dachshund | 86 | 31.62% | 221 | 38.91% | 62 | 0.99 | 0.99 | 6.5 |
Bulldog, French | 20 | 7.35% | 81 | 24.69% | 40 | 0.94 | 0.01 | 3.7 |
Miniature Pinscher | 6 | 2.21% | 29 | 20.69% | 0 | 0.00 | 0.00 | 10.3 |
Pekingese | 3 | 1.10% | 17 | 17.65% | 1 | 0.50 | 0.88 | 6.1 |
Basset Hound | 5 | 1.84% | 36 | 13.89% | 1 | 0.83 | 1.00 | 5.5 |
Beagle | 9 | 3.31% | 65 | 13.85% | 8 | 1.00 | 0.00 | 7.9 |
Welsh Corgi, Pembroke | 6 | 2.21% | 54 | 11.11% | 6 | 0.92 | 1.00 | 7.0 |
Maltese | 5 | 1.84% | 65 | 7.69% | 4 | 0.39 | 1.00 | 6.3 |
Shih Tzu | 7 | 2.57% | 92 | 7.61% | 11 | 0.56 | 0.92 | 6.9 |
Bichon Frise | 4 | 1.47% | 59 | 6.78% | 4 | 0.50 | 0.75 | 8.2 |
Chihuahua | 9 | 3.31% | 136 | 6.62% | 16 | 0.48 | 0.70 | 6.0 |
Pit Bull Terrier | 6 | 2.21% | 119 | 5.04% | 5 | 0.14 | 0.00 | 8.0 |
Cocker Spaniel, American | 3 | 1.10% | 61 | 4.92% | 1 | 1.00 | 0.00 | 7.0 |
Doberman Pinscher | 3 | 1.10% | 70 | 4.29% | 6 | 0.00 | 0.00 | 7.8 |
Rottweiler | 4 | 1.47% | 107 | 3.74% | 1 | 0.00 | 0.00 | 5.7 |
Mixed Breed | 46 | 16.91% | 1316 | 3.50% | 81 | 0.56 | 0.44 | 5.5 |
German Shepherd | 5 | 1.84% | 214 | 2.34% | 5 | 0.05 | 0.00 | 6.9 |
Other | 33 | 12.13% | 1430 | 2.31% | 40 | 0.25 | 0.23 | 7.7 |
Labrador Retriever | 12 | 4.41% | 568 | 2.11% | 5 | 0.03 | 0.00 | 8.5 |
Total | 272 | 4740 | 297 | 0.636 | 0.509 | 6.4 |
Age at IVDD Surgery | Univariable (Unadjusted) Linear Regression | Multivariable (Adjusted) Linear Regression | ||||||
---|---|---|---|---|---|---|---|---|
Mean | SE | Difference 1 | 95% CI | p | Difference 1 | 95% CI | p | |
12-FGF4RG | ||||||||
zero copies | 102.6 | 2.7 | Reference | Reference | ||||
one copy | 73.5 | 3 | −29.1 | −37.1 to −21.0 | <0.001 | −26.6 | −35.9 to −17.2 | <0.001 |
two copies | 73 | 2 | −29.5 | −36.4 to −22.7 | −31.2 | −40.5 to −21.8 | ||
Breed | ||||||||
Mixed breed | 74.7 | 3.2 | Reference | 0.0 to 16.2 | Reference | 2.6 to 23.3 | ||
Dachshund | 82.8 | 2.7 | 8.1 | −35.8 to −14.8 | <0.001 | 12.9 | −36.7 to −12.1 | <0.001 |
French bulldog | 49.4 | 3.1 | −25.3 | 8.0 to 22.7 | −24.4 | −2.1 to 13.4 | ||
Other purebred | 90.1 | 2.3 | 15.4 | 5.7 | ||||
Body weight (5 kg) | 80.4 | 1.5 | 1.6 | 0.3 to 2.9 | 0.017 | −2.2 | −3.8 to −0.6 | 0.008 |
18-FGF4RG | ||||||||
zero copies | 82.1 | 2.4 | Reference | −22.1 to −3.2 | Reference | −23.5 to −2.6 | ||
one copy | 69.4 | 3.9 | −12.7 | −6.3 to 6.3 | 0.02 | −13.1 | −14.7 to 3.7 | 0.049 |
two copies | 82.1 | 2.2 | 0 | −5.5 | ||||
Sex | ||||||||
Female | 78 | 2.4 | Reference | 0.158 | ||||
Male | 82.3 | 1.9 | 4.3 | −1.7 to 10.3 | ||||
Reproductive Status | ||||||||
Intact | 82.1 | 3.8 | Reference | 0.639 | ||||
Spayed/Neutered | 80.1 | 1.6 | −2.0 | −10.4 to 6.4 |
Diagnosis | Count | Median Weight (kg) | Median Age at Surgery (Years) | 12-FGF4RG Frequency | 18-FGF4RG Frequency |
---|---|---|---|---|---|
Group A | 378 | 8.1 | 5.5 | 0.765 | 0.587 |
Group B | 47 | 25.0 | 9.0 | 0.149 | 0.160 |
Univariable Logistic Regression | Multivariable Logistic Regression | |||||
---|---|---|---|---|---|---|
OR | 95%CI | p | OR | 95%CI | p | |
12-FGF4RG | ||||||
zero copies | Reference | <0.001 | Reference | <0.001 | ||
one copy | 7.75 | 4.04 to 14.84 | 6.02 | 2.75 to 13.18 | ||
two copies | 24.64 | 13.67 to 44.42 | 14.82 | 6.46 to 34.04 | ||
Age at IVDD, year | 0.81 | 0.75 to 0.87 | <0.001 | 0.88 | 0.80 to 0.95 | 0.003 |
Breed | ||||||
Mixed breed | Reference | <0.001 | Reference | 0.035 | ||
Dachshund | 5.8 | 2.70 to 12.47 | 1.82 | 0.61 to 5.39 | ||
French Bulldog | 1.46 | 0.69 to 3.09 | 0.36 | 0.13 to 1.02 | ||
Other purebred | 0.42 | 0.24 to 0.72 | 0.72 | 0.34 to 1.51 | ||
18-FGF4RG | ||||||
zero copies | Reference | Reference | ||||
one copy | 1.88 | 0.94 to 0.374 | <0.001 | 0.66 | 0.26 to 1.70 | 0.641 |
two copies | 4.37 | 2.80 to 6.83 | 1.04 | 0.49 to 2.20 | ||
Body weight (5 kg) | 0.78 | 0.70 to 0.84 | <0.001 | - | - | - |
Male sex | 0.99 | 0.67 to 1.47 | 0.96 | - | - | - |
Spayed or neutered | 2.1 | 1.23 to 3.56 | 0.006 | - | - | - |
Univariable Logistic Regression | Multivariable Logistic Regression | |||||
---|---|---|---|---|---|---|
OR | 95%CI | p | OR | 95%CI | p | |
12-FGF4RG | ||||||
zero copies | Reference | - | <0.001 | Reference | - | <0.001 |
one copy | 18.38 | 8.51 to 43.26 | 18.42 | 7.44 to 50.26 | ||
two copies | 43.11 | 15.10 to 129.8 | 44.23 | 12.92 to 163.3 | ||
18-FGF4RG | ||||||
zero copies | Reference | - | <0.001 | Reference | - | 0.079 |
one copy | 4.9 | 2.36 to 10.19 | 3.05 | 1.14 to 8.34 | ||
two copies | 7.7 | 3.25 to 17.46 | 2.3 | 0.77 to 6.90 | ||
Body weight (5 kg) | 0.7 | 0.59 to 0.81 | <0.001 | 1.15 | 0.92 to 1.44 | 0.22 |
Male sex | 1.33 | 0.73 to 2.48 | 0.355 | - | - | - |
Breed | Total Dogs | 12-FGF4RG Allele Frequency | Relative Risk | 95% CI | p Value |
---|---|---|---|---|---|
Shih Tzu | 52 | 0.25 | 10.3 | 1.8–62.1 | 0.005 |
Bichon Frise | 39 | 0.18 | 10.0 | 1.7–60.1 | 0.011 |
Mixed breed | 508 | 0.10 | 15.1 | 7.6–29.9 | <0.0001 |
Chihuahua | 60 | 0.10 | 5.5 | 1.7–18.2 | 0.008 |
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Batcher, K.; Dickinson, P.; Giuffrida, M.; Sturges, B.; Vernau, K.; Knipe, M.; Rasouliha, S.H.; Drögemüller, C.; Leeb, T.; Maciejczyk, K.; et al. Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes 2019, 10, 435. https://doi.org/10.3390/genes10060435
Batcher K, Dickinson P, Giuffrida M, Sturges B, Vernau K, Knipe M, Rasouliha SH, Drögemüller C, Leeb T, Maciejczyk K, et al. Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes. 2019; 10(6):435. https://doi.org/10.3390/genes10060435
Chicago/Turabian StyleBatcher, Kevin, Peter Dickinson, Michelle Giuffrida, Beverly Sturges, Karen Vernau, Marguerite Knipe, Sheida Hadji Rasouliha, Cord Drögemüller, Tosso Leeb, Kimberly Maciejczyk, and et al. 2019. "Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs" Genes 10, no. 6: 435. https://doi.org/10.3390/genes10060435
APA StyleBatcher, K., Dickinson, P., Giuffrida, M., Sturges, B., Vernau, K., Knipe, M., Rasouliha, S. H., Drögemüller, C., Leeb, T., Maciejczyk, K., Jenkins, C. A., Mellersh, C., & Bannasch, D. (2019). Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs. Genes, 10(6), 435. https://doi.org/10.3390/genes10060435