Categories: Limbs / fins / digit / tail phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602151 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2018

Species-specific name: Robinow-like syndrome; curly tail

Inheritance: Mansour et al. (2018): "Segregation of the caudal vertebral column malformations and genotype at DVL2 was consistent with a fully penetrant recessive mode of inheritance in Boston Terriers, Shih Tzus, Pit Bulls and mixed breeds ... . Segregation of the thoracic vertebral malformations was consistent with a recessive mode of inheritance with variable penetrance between breeds. In order to evaluate the molecular contribution to brachycephalic skull shape, the DVL2 mutant breeds were genotyped for the previously identified brachycephaly associated Line insertion affecting SMOC 2 splicing. Bulldogs and French Bulldogs were homozygous for the variant and the Boston Terriers had an allele frequency of 90.3% ... . Similar allele frequency for the BMP3 missense mutation was also reported for these three breeds indicating that they are homozygous or have a high allele frequency for three mutations that affect head shape [Schoenebeck et al., 2012].

Mapping: Jones et al. (2008) conducted an across-breed GWAS on 2,801 dogs from 147 breeds, each genotyped for 674 equally spaced SNPs, plus an additional 862 SNPs located in regions of interest. The results highlighted regions on CFA1, 9, 25 and 38. By conducting a mammoth proof-of-principle GWAS on "11 [breeds] with curly tails and 7 [breeds] with straight tails", with each dog being genotyped with Illumina CanineHD array (yielding 157,393 SNPs for analysis) developed for this study, Vaysse et al. (2011) highlighted a region between 96.26 and 96.96Mb on chromosome CFA1, which is flanked by the genes RCL1 and JAK2.

Molecular basis: Mansour et al. (2018) " identified a frameshift mutation in the WNT pathway gene DISHEVELLED 2 (DVL2) ... as the most strongly associated [with screw tail] variant in the canine genome ... . DVL2 cDNA was sequenced from the skeletal muscle of a dog with a normal tail and a screw tail Bulldog ... to confirm the presence of the mutation in the mRNA in the Bulldog sample (DVL2c.2044delC). ... This deletion is predicted to lead to a frameshift mutation, causing a premature stop codon that truncates the translated protein by 23 amino acids (p.Pro684LeufsX26)."

Clinical features: Mansour et al. (2018): "One group of three breeds (Bulldog, French Bulldog and Boston Terrier) is characterized by a wide head, short muzzle, widely spaced eyes, small size and abnormalities of the vertebral bones of the back and tail. These breeds are referred to as the screw tail breeds since the characteristic that is unique and easy to see in these breeds is their shortened and kinked tails." Niskanen et al. (2021): "The DVL2 variant segregates in a recessive manner with caudal vertebral malformations and has incomplete and variable penetrance for thoracic vertebral malformations (Mansour et al. 2018). ... With CT examinations in American Staffordshire Terriers, we confirmed that the DVL2 allele is associated with caudal vertebral malformations and a brachycephalic phenotype. We also hypothesize that the variant may be linked to additional health conditions, including brachycephalic obstructive airway syndrome and congenital heart defects."

Prevalence: Mansour et al. (2018): "This DVL2 variant was fixed in Bulldogs and French Bulldogs and had a high allele frequency (0.94) in Boston Terriers." These same authors also reported that "To confirm the association of the DVL2c.2044delC mutation with the screw tail phenotype, 667 dogs, from 49 breeds, were genotyped for the DVL2 mutation . . . . 177 dogs were from the screw tail breeds including 33 Bulldogs, 79 French Bulldogs and 65 Boston Terriers. All were homozygous for the mutant allele except 6 of the Boston Terriers (4 heterozygous, 2 wildtype). In addition, we identified dogs from several other breeds, including Pit bulls, Staffordshire Bull Terrier, Shih Tzu and mixed breeds, that are heterozygous or homozygous for the DLV2 mutation. The Pug breed has sometimes been classified with the screw tail breeds due to its curled tail; however, the tail is full length and does not have caudal vertebral malformations . . . . 29 Pugs tested were wild-type for the DVL2 mutation. Likewise, the Pug dogs do not share the high MAF with the screw tail breeds around the DVL2 mutation . . . . Three hundred and eighty five dogs from 43 other breeds were also tested and were all wild-type."

Breeds: American Bulldog (Dog) (VBO_0200034), American Pit Bull Terrier (Dog) (VBO_0200054), American Staffordshire Terrier (Dog) (VBO_0200055), Boston Terrier (Dog) (VBO_0200204), Dogue de Bordeaux (Dog) (VBO_0200450), English Bulldog (Dog) (VBO_0200485), French Bulldog (Dog) (VBO_0201455), Pug (Dog) (VBO_0201089), Shih Tzu (Dog) (VBO_0201223), Staffordshire Bull Terrier (Dog) (VBO_0201296).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: