Categories: Limbs / fins / digit / tail phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611554 (trait) , 611553 (trait) , 164760 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive lethal

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Species-specific symbol: wg-2

History: Webb et al. (2018): "The wingless-2 (wg-2) mutation was originally identified at the University of Connecticut in a flock of chickens synthesized from Rhode Island Red, White Leghorn, Dorking breeds, and Red Jungle Fowl (Zwilling, 1956) . . . Wg-2 was the second wingless mutation characterized in the chicken; the first, now extinct, exhibited a similar phenotype and additionally was described as having incomplete or absent lungs, air sacs, and kidneys (Waters and Bywaters, 1943)" [see OMIA 001073-9031 for details of the original wingless mutant]. Webb et al. (2018) also reported that "In the late 1980s at the University of California Davis (UCD), a congenic inbred line was established by introgression of wg-2 in order to advance mapping and gene analysis research at a time wherein genomic tools were barely envisioned, much less the advent of the chicken sequencing project to advance poultry and vertebrate biology. The Wingless-2.331 (Wg-2.331) congenic inbred line was derived by first crossing known wg-2 carriers (+/wg-2) into the UCD 331.003 congenic line (Abplanalp et al., 1992; Pisenti et al., 1999). The +/wg-2 carrier progeny were confirmed by test-mating and then used to backcross to the parent line UCD 331.003. The backcross method using confirmed carrier (+/wg-2) progeny was repeated for at least 7 generations, with 2 additional backcrosses after the line was closed to improve fertility and viability, as per available breeding records and personal communications. This labor-intensive multi-year strategy placed the wg-2 locus in a uniform genetic background (99+% inbred) such that only the introgressed region containing the mutation along with other normal polymorphisms differs between normal (+/+ or +/wg-2) and mutant (wg-2/wg-2) individuals. The line was closed (inter se matings only) and perpetuated using +/wg-2 parents as breeders after being verified by test crosses. Over more than 60 yr of breeding, Mendelian ratios fit an autosomal recessive pattern of inheritance for the wg-2 mutation."

Inheritance: Citing Somes (1990) and Pisenti (1995), Webb et al. (2018) stated that the wg-2 "mutation is inherited in an autosomal recessive pattern and is an embryonic lethal".

Mapping: Webb et al. (2018) mapped this disorder "to a 227 kb candidate region on chicken chromosome 12".

Molecular basis: By sequencing the positional candidate region on chromosome GGA12 identified by Webb et al. (2018), in chickens from the powerful congenic line described in the History section above, Youngworth and Delany (2019) identified a likely causal variant as "a cytosine to thymine transition, resulting in a predicted stop codon in the transcript for RAF1 in wg-2/wg-2 individuals".

Clinical features: Youngworth and Delany (2019): "The phenotype of affected homozygous mutants is characterized by absent forelimbs, truncated hindlimbs, craniofacial malformations such as clefting or cross beak, and kidney and severe skin/feather malformations".

Associated gene: