Auditory-pigmentary syndrome, PAX3 -related

 

Gene: PAX3

Transmission: Autosomal, dominant (incomplete)

The animal only has to have one copy of the mutation to be at risk of developing hypertrophic cardiomyopathy.  Animals with two copies of the mutation generally have more severe symptoms and an earlier onset of the disease than animals with just one copy of the mutation.  Offspring are potentially at risk of developing the disease if at least one parent carries the mutation.  Alternatively, the disease is caused by a de novo mutation.

Mutations:

Mutation Splashed White 2 (SW2: Lipizzan, Noriker, Quarter Horse): Substitution, PAX3 gene; c.209 G>A, p.(Cys70Tyr), chromosome 6.

Mutation Splashed White 4 (SW4: Appaloosa): Substitution, PAX3 gene; c.95 C>G, p.(Pro32Arg), chromosome 6.

Mutation Splashed White 10 (SW10: Purebred Spanish): Substitution (nonsense), PAX3 gene; c.583 C>T, p.(Arg195 STOP), chromosome 6.

Breeds: American Paint Horse, Appaloosa, Noriker, Purebred Spanish, Quarter Horse

Medical system: Deafness, dermal (pigmentation)

Age of onset of symptoms: From birth.

Horses are noted for their wide variety of white spotting phenotypes, ranging from isolated small white spots to a completely white horse.  Melanocytes are the mature cells responsible for pigment production in the skin.  They are derived developmentally from a population of embryonic cells called neural crest cells.  Mutations in a large group of genes (EDNRB, KIT, MITF, PAX3, TRPM1, RFWD3 and HPS5) can cause a failure of neural crest cells to survive or migrate properly during embryogenesis, resulting in regional lack of melanocytes in the skin and thus in white spotting. Neural crest cells also contribute to other cell populations, and some of the mutations that give white spotting can be involved in additional phenotypes including deafness, ocular problems, intestinal problems, infertility and indeed embryo lethality.  For example, the presence of melanocytes within the stria vascularis of the cochlear duct is important for proper hearing.

The Splashed White (SW) phenotypes in the horse are a white spotting pattern characterized by white legs and belly as if the animal had been dipped or splashed in white paint.  Mutations in two genes, PAX3 and MITF, can be responsible for the SW phenotypes.  Both PAX3 and MITF genes code for transcription factors important for neural crest cell migration and survival; indeed, the product of the PAX3 gene is important for the expression of the MITF gene.  Mutations in either PAX3 or MITF can be associated with deafness.  Three mutations in the PAX3 gene are associated with splashed white markings and with blue eyes when heterozygous.  One copy of the SW2 mutation is known to be associated with deafness with variable penetration, while two copies can give a completely white animal.  The SW4 and SW10 PAX3 mutations may be embryo lethal when homozygous. Slashed White pigmentation patterns caused by MITF mutations (SW1, SW3, SW5, SW6, SW7, SW8) are also associated with deafness.

Veterinarians and breeders should be aware of the possible health associations with the Splashed White phenotypes.  More studies are warranted.  DNA tests are available for the different SW mutations.

 

References:

OMIA link: [1688-9796], [0214-9796]

Durward-Akhurst SA, Marlowe JL, Schaefer RJ, et al. (2024) Predicted genetic burden and frequency of phenotype-associated variants in the horse. Sci Rep 14:8396.  [pm/38600096]

McFadden A, Vierra M, Martin K, et al. (2024) Spotting the pattern: A review on white coat color in the domestic horse. Animals (Basel) 14:451.  [pm/38338094]

McFadden A, Martin K, Foster G, et al. (2023) Two novel variants in MITF and PAX3 associated with splashed white phenotypes in horses. J Equine Vet Sci 128:104875.  [pm/37406837]

Druml T, Grilz-Seger G, Neuditschko M, et al. (2018) Novel insights into Sabino1 and splashed white coat color patterns in horses. Anim Genet 49:249-253.  [pm/29635692]

Dürig N, Jude R, Jagannathan V, Leeb T. (2017) A novel MITF variant in a white American Standardbred foal. Anim Genet 48:123-124, 2017.  [pm/27592871]

Hauswirth R, Haase B, Blatter M, et al. (2012) Mutations in MITF and PAX3 cause “splashed white” and other white spotting phenotypes in horses. PLoS Genet 8(4):e1002653. [pm/22511888]

Magdesian KG, Williams DC, Aleman M, et al. (2009) Evaluation of deafness in American Paint Horses by phenotype, brainstem auditory-evoked responses, and endothelin receptor B genotype. J Am Vet Med Assoc 235:1204-11.  [pm/19912043]

 

Contributed by: Mélody Nault and Julie-Pier Rousseland, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)