In other species: domestic cat , cattle , chicken , pig , turkey , domestic guinea pig , goat , guanaco , Arabian camel , Western roe deer , horse , springbok , rock pigeon , sheep , llama , alpaca

Categories: Limbs / digit / tail phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 174500 (trait) , 605522 (gene) , 188740 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2008

Cross-species summary: Often called preaxial polydactyly (PPD)

Species-specific name: Dew claws, canine preaxial polydactyly

Species-specific symbol: PPD

Mapping: Park et al. (2004) mapped dew claws (an extra first digit on the hind limb) in the Korean breed Sapsaree to canine chromosome 16. The maximum two-point lod score of 20.76 was obtained for microsatellite markers REN85M08/REN85N14. Finemapping via haplotype analysis refined the location of the dewclaw locus to an interval delimited by markers UCMCF12 and CXX876.

Park et al. (2008): "The candidate locus was further limited to a linkage disequilibrium (LD) block of <213 kb composing the single gene, LMBR1, by LD mapping with single nucleotide polymorphisms (SNPs) for affected individuals from both Korean and Western breeds." In several species, polydactyly results from mutations in the ZPA regulatory sequence (ZRS), an enhancer of the developmental gene Sonic Hedgehog (SHH). ZRS is located in intron 5 of the LMBR1 gene.

Molecular basis: Park et al. (2008) identified within the two identified distinct affected haplotypes for Asian and Western breeds two different single-base changes in the upstream sequence (pZRS) of the ZRS. A G to A variant named DC-1 was found in the 1-kb region upstream of the 5′-end of the ZRS in 150 affected Sapsaree (144 affected dogs were heterozygous G/A and 6 affected dogs homozygous A/A) and six affected Korean Tosas, whereas 65 unaffected Sapsaree dogs were homozygous G/G. DC-1 was invariable (G/G) in 42 dogs of several Western breeds which included dogs with and without dew claws.

Another G/A variant (named DC-2), located 246 bp downstream of DC-1, was identified as the likely causal variant for PPD in 26 affected dogs of Western breeds (including, Beagle, Cocker Spaniel, Malinois, Rottweiler, Shetland Sheepdog, Standard Poodle, Standard Schnauzer, Shih Tzu, and Yorkshire Terrier). 14 affected dogs were heterozygous G/A and 12 affected dogs homozygous A/A, whereas 23 unaffected individuals from the same breeds were homozygous G/G.

Park et al. (2008) “investigated the role of the ZRS in transcriptional regulation by generating a luciferase reporter construct. … the core ZRS region displaying almost 100% identity in mammalian sequences exhibited the highest enhancer activity …. When we introduced DC-1 or DC-2 mutations in the wild-type ZRS region, >50% reduction in enhancer activity was evident ….”

Kropatsch et al. (2015) identified that Norwegian Lundehund, a breed that is characterised by the presence of extra toes in the fore and hind limbs, were homozygous A/A for the DC-2 variant identified by Park et al. (2008). This provided further support that this variant is causing canine PPD.

However, other suspected genetic causes for polydactyly have been reported in dogs. Fondon and Garner (2004) investigated repeat expansion or contraction alleles in selected genes and analysed their association with morphometric traits. They noted that a 51bp deletion in the Alx4 gene occurred in homozygosity in four Great Pyrenees, a breed in which bilateral rear first digit polydactyly is common. Alx4 is known to cause polydactyly in mice. The deletion was not present in dogs from other breeds investigated in this study and was also absent in a single Great Pyrenees without polydactyly. The authors state that hind limb polydactyly in Great Pyreneesis is not a simple Mendelian trait but concluded that polydactyly in this breed is likely caused in part by the 17-aa deletion.

Clinical features: Park et al. (2008): “Canine preaxial polydactyly (PPD) in the hind limb is a developmental trait that restores the first digit lost during canine evolution. … As described previously (Park et al. 2004), the restored phenotype is slightly overmanifested, generating one or more preaxial digits. As a matter of fact, the external morphology of hind-limb-specific canine PPD is slightly different from other polydactylies in that only the claw is observed as having an extra digit with fibrous tissue connecting the region between the tarsal and the first metatarsal bones, which either is reduced in size or is incomplete with a lesser deposit of bony material (Miller 1979; Park et al. 2004).”

Breeds: Beagle, Cocker Spaniel, Great Pyrenees, Korean Tosa, Malinois, Rottweiler, Saint Bernard, Sapsaree, Shetland Sheepdog, Shih-Tzu, Standard Poodle, Standard Schnauzer, Yorkshire Terrier.

Associated genes: