In other species: horse

Categories: Pigmentation phene , Hearing / vestibular / ear phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 193500 (trait) , 148820 (trait) , 606597 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2024

Cross-species summary: The name of this phene was changed from "Coat colour, white spotting, PAX3-related" to "Auditory-pigmentary syndrome, PAX3-related" on 01-Mar-2024.
The phene includes altered pigmentation of the eyes and/or skin together with a predisposition for unilateral or bilateral sensineural deafness. Affected animals often have blue eyes or eyes with different colors (heterochromia iridis). Skin pigmentation may include variable degrees of white spotting ranging from tiny white spots up to completely white animals. The absence of pigment is caused by the absence of melanocytes ("leucism"), not by a failure in the biochemical reactions required for pigment synthesis. The increased risk for deafness is the consequence of lacking melanocytes in the stria vascularis of the inner ear.

Species-specific name: Dominant blue eyes (DBE)

Species-specific symbol: DBE; DBE^CEL (Celestial Dominant Blue Eyes); DBE^RE (Rociri Elvis Dominant Blue Eyes); DBE^ALT (Altai Dominant Blue Eye)

Species-specific description: Abitbol et al. (2024, PMID:38644700): “minimal white spotting associated with blue eyes was selected by feline breeders to create the Altai, Topaz, and Celestial breeds. Various established breeds also introduced this trait in their lineages. The trait, that was confirmed as autosomal dominant by breeding data, was first described in domestic cats from Kazakhstan and Russia, in British shorthair and British longhair from Russia, and in Maine Coon cats from the Netherlands, suggesting different founding effects.”

Mapping: Abitbol et al. (2024,PMID:38644700): “Using a genome-wide association study [the authors] identified a single region on chromosome C1 that was associated with the minimal white spotting and blue eyes phenotype (also called DBE by breeders for dominant blue eyes) in the French Celestial breed. Within that region we identified Paired Box 3 (PAX3) as the strongest candidate gene, since PAX3 is a key regulator of MITF (Melanocyte-Inducing Transcription Factor) and PAX3 variants have been previously identified in various species showing white spotting with or without blue eyes including the mouse and the horse.” See also OMIA:001688-9796 : Auditory-pigmentary syndrome, PAX3-related in Equus caballus (horse)            

Molecular basis: Abitbol et al. (2024, PMID:38644700): “Whole genome sequencing of a Celestial cat revealed an endogenous retrovirus LTR (long terminal repeat) insertion [NC_018730.3:g.206974029_206974030insN[395] ] within PAX3 intron 4 known to contain regulatory sequences (conserved non-coding element [CNE]) involved in PAX3 expression. The insertion is in the vicinity of CNE2 and CNE3. All 52 Celestial and Celestial-mixed cats with a DBE phenotype presented the insertion, that was absent in their 22 non-DBE littermates and in 87 non-DBE cats from various breeds. … the variant was found in nine DBE Maine Coon cats [Topaz line] related to the Celestial founder and four DBE Siberian cats with an uncertain origin. Segregation of the variant in the Celestial breed is consistent with dominant inheritance and does not appear to be associated with deafness.”
Rudd Garces et al. (2024) identified a different likely causal variant in PAX3 in the Maine Coon Dutch line with dominant blue eyes (iris hypopigmentation) and incomplete penetrance deafness and minimal white spotting: "a heterozygous nonsense single base pair substitution in exon 6 of PAX3 (NC_051841.1:g.205,787,310G>A, XM_019838731.3:c.937C>T, XP_019694290.1:p.Gln313*) ... [and]  propose the designation of DBE^RE (Rociri Elvis Dominant Blue Eyes) ... ." The DBE^RE was not present in DBE cats of the Topaz lineage. 
Abitbol et al. (2024, PMID:38997957) report a third likely causal variant: "an RD-114 retrovirus LTR (long terminal repeat) insertion within PAX3 intron 4 (namely NC_018730.3:g.206975776_206975777insN[433]) ... [and] propose that this NC_018730.3:g.206975776_206975777insN[433] variant represents the DBE^ALT (Altai Dominant Blue Eye) allele in the domestic cat."

Clinical features: Abitbol et al. (2024, PMID: 38997957) report that DBE "includes one or two blue eyes or particolored eyes and minimal white spotting. Different feline breeding lines were developed for DBE, and in some lineages, deafness has been identified as being associated with this trait."  
Rudd Garces et al. (2024) report that some Main Coon cats with dominant blue eyes exhibited signs of deafness. The authors suspect that homozygosity for the PAX3:c.937C>T [DBE^RE, omia.variant:1659] allele may result in embryonic or fetal lethality.

Control: Rudd Garces et al. (2024) conclude that "the mating of 2 heterozygous PAX3:c.937C>T [DBE^RE, omia.variant:1659] cats is not recommended in order to avoid the accidental production of an embryo homozygous for this allele. Additionally, mating a carrier with a wild-type animal is also not recommended to prevent the birth of blue-eyed deaf cats."

Breeds: Altai (Cat) (VBO_0100259), British Longhair (Cat) (VBO_0100051), British Shorthair (Cat) (VBO_0100052), Celestial, Chinese Tank Cat (Cat) (VBO_0100072), Maine Coon (Cat) (VBO_0100154), Persian (Cat) (VBO_0100188), Ragdoll (Cat) (VBO_0100196), Siberian (Cat) (VBO_0100223), Sphynx (Cat) (VBO_0100230).
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: