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