OMIA:001474-9615 : Rupture of the cranial cruciate ligament in Canis lupus familiaris (dog)

Categories: Skeleton phene (incl. short stature & teeth)

Links to MONDO diseases: No links.

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: no

Species-specific name: cranial cruciate ligament rupture; CCL disease; anterior cruciate ligament rupture; cranial cruciate ligament disease; cruciate disease

Species-specific symbol: RCCL, CCLR

Inheritance: Wilke et al. (2006) showed that this disorder is heritable, but the form of inheritance remains to be determined. GWAS conducted by Baker et al. (2017) and Hayward et al. (2019) established the multifactorial nature of this disorder, with numerous QTL reported.

Mapping: Hayward et al. (2019) reported a QTL of relatively large effect "on CFA20: 42,827,199 . . . in the gene LIM Domain-Containing 1 (LIMD1), which is involved in regulating stress osteoclastogenesis, and osteoblast function and differentiation" Baker et al. (2021): "leveraged the dog model with Bayesian mixture model (BMM) analysis (BayesRC) to identify novel and relevant genetic variants associated with ACL rupture. We performed RNA sequencing of ACL and synovial tissue and assigned single nucleotide polymorphisms (SNPs) within differentially expressed genes to biological prior classes. SNPs with the largest effects were on chromosomes 3, 5, 7, 9, and 24. Selection signature analysis identified several regions under selection in ACL rupture cases compared to controls. These selection signatures overlapped with genome-wide associations with ACL rupture as well as morphological traits. Notable findings include differentially expressed ACSF3 with MC1R (coat color) and an association on chromosome 7 that overlaps the boundaries of SMAD2 (weight and body size)." Lee et al. (2023): "Multivariate analysis of ACL rupture case and control Labrador Retrievers of differing coat color revealed associations with several ACL rupture candidate genes after GEMMA and mvBIMBAM analysis, consistent with a polygenic disease. This study validated ACSF3 and DZIP1L [Baker et al. 2021] as candidate genes, discovered other novel candidate loci, and revealed association with many genes in a chromosome 5 locus."

Markers: Baird et al. (2004): "A candidate gene, single nucleotide polymorphism (SNP) genotyping approach ...was designed to investigate several CCLR-susceptible dog breeds and identify CCLR-associated genes/gene regions ... . We identified SNPs in key genes involved in ligament strength, stability and extracellular matrix formation (COL5A1, COL5A2, COL1A1, COL3A1, COL11A1, COL24A1, FBN1, LOX, LTBP2) which were significantly associated with CCLR susceptibility across the dog breeds used in this study ...."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Breeds: Bichon Frise (Dog) (VBO_0200163), Labrador Retriever (Dog) (VBO_0200800), Newfoundland (Dog) (VBO_0200938), Rottweiler (Dog) (VBO_0201143), Staffordshire Bull Terrier (Dog) (VBO_0201296).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:001474-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2024 Dan, M.J., Wills, D.J., Crowley, J.D., Cance, N., Romandini, I., Walsh, W.R., Dejour, D.H. :
Anterior cruciate ligament zoobiquity: Can man's best friend tell us we are being too cautious with the implementation of osteotomy to correct posterior tibial slope. Knee Surg Sports Traumatol Arthrosc , 2024. Pubmed reference: 38509848. DOI: 10.1002/ksa.12109.
2023 Engdahl, K., Bergström, A., Höglund, O., Moldal, E.R., Emanuelson, U., Boge, G.S. :
Long-term outcome in dogs with cranial cruciate ligament disease evaluated using the canine orthopaedic index. Vet Rec :e3172, 2023. Pubmed reference: 37439319. DOI: 10.1002/vetr.3172.
Fung, C., Ficklin, M., Okafor, C.C. :
Associations between meniscal tears and various degrees of osteoarthritis among dogs undergoing TPLO for cranial cruciate ligament rupture. BMC Res Notes 16:36, 2023. Pubmed reference: 36915203. DOI: 10.1186/s13104-023-06307-0.
Hayward, J.J., Todhunter, R.J. :
Common orthopedic traits and screening for breeding programs. Vet Clin North Am Small Anim Pract 53:1013-1029, 2023. Pubmed reference: 37225647. DOI: 10.1016/j.cvsm.2023.04.004.
Hynes, J., Manfredi, J.M., Shull, S.A. :
Cranial cruciate ligament disease is perceived to be prevalent and is misunderstood in field trial sport. J Am Vet Med Assoc :1-6, 2023. Pubmed reference: 37451677. DOI: 10.2460/javma.23.01.0004.
Langenbach, A. :
Evaluating the relationship between osteoarthritis and cruciate ligament disease in dogs. Vet Rec 192:289-291, 2023. Pubmed reference: 37000719. DOI: 10.1002/vetr.2920.
Lee, B.T., Baker, L.A., Momen, M., Terhaar, H., Binversie, E.E., Sample, S.J., Muir, P. :
Identification of genetic variants associated with anterior cruciate ligament rupture and AKC standard coat color in the Labrador Retriever. BMC Genom Data 24:60, 2023. Pubmed reference: 37884875. DOI: 10.1186/s12863-023-01164-z.
Miles, J.E., Brønniche Møller Nielsen, M. :
Reported accuracy of cranial closing wedge ostectomy variants for management of canine cranial cruciate ligament insufficiency: A systematic review and meta-analysis. Vet J :105989, 2023. Pubmed reference: 37148995. DOI: 10.1016/j.tvjl.2023.105989.
Pegram, C., Brodbelt, D.C., Diaz-Ordaz, K., Chang, Y., von Hekkel, A.F., Church, D.B., O'Neill, D.G. :
Risk factors for unilateral cranial cruciate ligament rupture diagnosis and for clinical management in dogs under primary veterinary care in the UK. Vet J :105952, 2023. Pubmed reference: 36708945. DOI: 10.1016/j.tvjl.2023.105952.
Waters, D.J., Fu, R., Carrillo, A.E., Chiang, E.C., Maras, A.H., Kengeri, S.S., Suckow, C.L. :
Correlates of estimated lifetime cruciate ligament survival inform potential rupture risk reduction strategies: findings from the Exceptional Aging in Rottweilers Study. Sci Rep 13:13920, 2023. Pubmed reference: 37626101. DOI: 10.1038/s41598-023-39288-y.
2022 Binversie, E.E., Momen, M., Rosa, G.J.M., Davis, B.W., Muir, P. :
Across-breed genetic investigation of canine hip dysplasia, elbow dysplasia, and anterior cruciate ligament rupture using whole-genome sequencing. Front Genet 13:913354, 2022. Pubmed reference: 36531249. DOI: 10.3389/fgene.2022.913354.
Binversie, E.E., Walczak, B.E., Cone, S.G., Baker, L.A., Scerpella, T.A., Muir, P. :
Canine ACL rupture: a spontaneous large animal model of human ACL rupture. BMC Musculoskelet Disord 23:116, 2022. Pubmed reference: 35123473. DOI: 10.1186/s12891-021-04986-z.
2021 Baker, L.A., Momen, M., McNally, R., Berres, M.E., Binversie, E.E., Sample, S.J., Muir, P. :
Biologically Enhanced Genome-Wide Association Study Provides Further Evidence for Candidate Loci and Discovers Novel Loci That Influence Risk of Anterior Cruciate Ligament Rupture in a Dog Model. Front Genet 12:593515, 2021. Pubmed reference: 33763109. DOI: 10.3389/fgene.2021.593515.
Engdahl, K., Emanuelson, U., Höglund, O., Bergström, A., Hanson, J. :
The epidemiology of cruciate ligament rupture in an insured Swedish dog population. Sci Rep 11:9546, 2021. Pubmed reference: 33953264. DOI: 10.1038/s41598-021-88876-3.
Jiang, L., Li, Z., Hayward, J.J., Hayashi, K., Krotscheck, U., Todhunter, R.J., Tang, Y., Huang, M. :
Genomic prediction of two complex orthopedic traits across multiple pure and mixed breed dogs. Front Genet 12:666740, 2021. Pubmed reference: 34630503. DOI: 10.3389/fgene.2021.666740.
2020 Anderson, K.L., Zulch, H., O'Neill, D.G., Meeson, R.L., Collins, L.M. :
Risk factors for canine osteoarthritis and its predisposing arthropathies: A systematic review. Front Vet Sci 7:220, 2020. Pubmed reference: 32411739. DOI: 10.3389/fvets.2020.00220.
Baker, L.A., Momen, M., Chan, K., Bollig, N., Lopes, F.B., Rosa, G.J.M., Todhunter, R.J., Binversie, E.E., Sample, S.J., Muir, P. :
Bayesian and machine learning models for genomic prediction of anterior cruciate ligament rupture in the canine model. G3 (Bethesda) 10:2619-2628, 2020. Pubmed reference: 32499222. DOI: 10.1534/g3.120.401244.
Cook, S.R., Conzemius, M.G., McCue, M.E., Ekenstedt, K.J. :
SNP-based heritability and genetic architecture of cranial cruciate ligament rupture in Labrador Retrievers. Anim Genet , 2020. Pubmed reference: 32696518. DOI: 10.1111/age.12978.
2019 Hayward, J.J., White, M.E., Boyle, M., Shannon, L.M., Casal, M.L., Castelhano, M.G., Center, S.A., Meyers-Wallen, V.N., Simpson, K.W., Sutter, N.B., Todhunter, R.J., Boyko, A.R. :
Imputation of canine genotype array data using 365 whole-genome sequences improves power of genome-wide association studies. PLoS Genet 15:e1008003, 2019. Pubmed reference: 31525180. DOI: 10.1371/journal.pgen.1008003.
Healey, E., Murphy, R.J., Hayward, J.J., Castelhano, M., Boyko, A.R., Hayashi, K., Krotscheck, U., Todhunter, R.J. :
Genetic mapping of distal femoral, stifle, and tibial radiographic morphology in dogs with cranial cruciate ligament disease. PLoS One 14:e0223094, 2019. Pubmed reference: 31622367. DOI: 10.1371/journal.pone.0223094.
2018 Baker, L.A., Rosa, G.J.M., Hao, Z., Piazza, A., Hoffman, C., Binversie, E.E., Sample, S.J., Muir, P. :
Multivariate genome-wide association analysis identifies novel and relevant variants associated with anterior cruciate ligament rupture risk in the dog model. BMC Genet 19:39, 2018. Pubmed reference: 29940858. DOI: 10.1186/s12863-018-0626-7.
2017 Baker, L.A., Kirkpatrick, B., Rosa, G.J., Gianola, D., Valente, B., Sumner, J.P., Baltzer, W., Hao, Z., Binversie, E.E., Volstad, N., Piazza, A., Sample, S.J., Muir, P. :
Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture. PLoS One 12:e0173810, 2017. Pubmed reference: 28379989. DOI: 10.1371/journal.pone.0173810.
Belanger, J.M., Bellumori, T.P., Bannasch, D.L., Famula, T.R., Oberbauer, A.M. :
Correlation of neuter status and expression of heritable disorders. Canine Genet Epidemiol 4:6, 2017. Pubmed reference: 28560045. DOI: 10.1186/s40575-017-0044-6.
Huang, M., Hayward, J.J., Corey, E., Garrison, S.J., Wagner, G.R., Krotscheck, U., Hayashi, K., Schweitzer, P.A., Lust, G., Boyko, A.R., Todhunter, R.J. :
A novel iterative mixed model to remap three complex orthopedic traits in dogs. PLoS One 12:e0176932, 2017. Pubmed reference: 28614352. DOI: 10.1371/journal.pone.0176932.
2014 Baird, A.E., Carter, S.D., Innes, J.F., Ollier, W.E., Short, A.D. :
Genetic basis of cranial cruciate ligament rupture (CCLR) in dogs. Connect Tissue Res 55:275-81, 2014. Pubmed reference: 24684544. DOI: 10.3109/03008207.2014.910199.
2013 Bellumori, T.P., Famula, T.R., Bannasch, D.L., Belanger, J.M., Oberbauer, A.M. :
Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995-2010). J Am Vet Med Assoc 242:1549-55, 2013. Pubmed reference: 23683021. DOI: 10.2460/javma.242.11.1549.
2009 Clements, DN., Short, AD., Barnes, A., Kennedy, LJ., Ferguson, JF., Butterworth, SJ., Fitzpatrick, N., Pead, M., Bennett, D., Innes, JF., Carter, SD., Ollier, WE. :
A candidate gene study of canine joint diseases. J Hered 101:54-60, 2009. Pubmed reference: 19965910. DOI: 10.1093/jhered/esp088.
Wilke, VL., Zhang, S., Evans, RB., Conzemius, MG., Rothschild, MF. :
Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands. Am J Vet Res 70:1013-7, 2009. Pubmed reference: 19645583. DOI: 10.2460/ajvr.70.8.1013.
2008 Witsberger, TH., Villamil, JA., Schultz, LG., Hahn, AW., Cook, JL. :
Prevalence of and risk factors for hip dysplasia and cranial cruciate ligament deficiency in dogs. J Am Vet Med Assoc 232:1818-24, 2008. Pubmed reference: 18598150. DOI: 10.2460/javma.232.12.1818.
2006 Wilke, VL., Conzemius, MG., Kinghorn, BP., Macrossan, PE., Cai, W., Rothschild, MF. :
Inheritance of rupture of the cranial cruciate ligament in Newfoundlands. J Am Vet Med Assoc 228:61-4, 2006. Pubmed reference: 16426167. DOI: 10.2460/javma.228.1.61.
2002 Harasen, G. :
Diagnosing rupture of the cranial cruciate ligament. Can Vet J 43:475-6, 2002. Pubmed reference: 12058576.

Edit History

  • Created by Frank Nicholas on 27 Oct 2009
  • Changed by Frank Nicholas on 18 Sep 2019
  • Changed by Imke Tammen2 on 20 Apr 2021
  • Changed by Imke Tammen2 on 27 Aug 2021
  • Changed by Imke Tammen2 on 28 Aug 2021
  • Changed by Imke Tammen2 on 23 May 2022
  • Changed by Imke Tammen2 on 27 Oct 2022
  • Changed by Imke Tammen2 on 01 Feb 2023
  • Changed by Imke Tammen2 on 03 Nov 2023