Androgen Insensitivity Syndrome (AIS)

Quick Summary

Five mutations in the androgen receptor gene, located on the X chromosome, are known to result in androgen insensitivity. Androgen insensitivity syndrome causes male horses to be sterile and appear phenotypically female.

Phenotype: In male horses, external genitalia fails to develop and is coupled with associated sterility.

Mode of Inheritance: X-linked recessive

Alleles: N = Normal; AR1, AR2, AR3, AR4, AR5 = Androgen receptor variants

Breeds appropriate for testing: Quarter Horse (AR1), Tennessee Walking Horse (AR4), Thoroughbred (AR2 and AR5), Warmbloods (AR3)

Explanation of results:

Males only have one X chromosome whereas females have two, therefore possible genotypes will differ by sex.

  • Female horses with the N/N genotype do not have any of the genetic variants that result in Androgen Insensitivity Syndrome and cannot transmit these AIS-associated variants to any of their offspring.
  • Female horses with the N/AR(1-5) genotype carry one copy of a genetic variant that results in Androgen Insensitivity Syndrome. They are predicted to transmit the variant to 50% of their offspring. All male offspring inheriting the affected allele will be sterile and will appear phenotypically female.
  • Female horses cannot be homozygous for the AR variants.
  • Males horses with the N genotype do not have any of the genetic variants that result in Androgen Insensitivity Syndrome.
  • Male horses with the AR1, 2, 3, 4 or 5 genotype have one copy of a genetic variant that results in Androgen Insensitivity Syndrome. Since males only have one copy of the gene, they will be sterile and will appear phenotypically female.
Price

$40 one test per animal

Additional Details

Sexual differentiation in mammals results from the presence and temporal expression of specific genes during development. In mammals, females are the homogametic sex, possessing two X chromosomes, while males are heterogametic, possessing one X and one Y chromosome. While most genes controlling sex determination are found on the sex chromosomes, not all genes controlling sexual differentiation are restricted to the X and Y chromosomes.

In development, the presence of genes on the Y chromosome triggers undifferentiated embryonic reproductive tissue to develop as testes. The developing testes subsequently produce hormones to complete male reproductive development. These circulating hormones bind to androgen receptors on the external surfaces of cells, resulting in development of additional essential male reproductive tissues. The androgen receptor gene (AR) is located on the X chromosome. Sequence variants in the androgen receptor gene (AR) may result in an inability of the circulating hormones to bind, thus preventing further induction of male development. Thus, horses with variants in AR are insensitive to the effects of androgen. This androgen insensitivity results in the remaining tissues failing to develop as male specific organs and can result in the presence of external female genitalia.

Five breed-specific variants in the AR gene are known to result in androgen insensitivity in the domestic horse: c.1A>G (AR1): Quarter Horse (Revay, et al 2012), c.2042G>C (AR2): Thoroughbred (Bolzon et al. 2016), c.1630_1654del (AR3): Warmbloods (Welsford et al. 2017), c.183delT (AR4): Tennessee Walking Horse (Villagomez et al. 2020), and c.2132C>T (AR5): Thoroughbred (Villagomez et al. 2020).

Since males, as the heterogametic sex, only have one X chromosome and AR is located on the X chromosome, only males are affected by AR1-5. The presence of any of the known androgen receptor variants will result in androgen insensitivity in a male foal. As females do not have testes-derived circulating hormones, non-functional androgen receptors have no developmental impact on them. However, since males with the variant are sterile, it is not possible for males to pass an affected AR allele to offspring and thus females cannot be homozygous for the AR variants.

The VGL offers a test for all five known variants, allowing for the detection of mares carrying the androgen insensitivity alleles and providing owners the opportunity to avoid producing AIS foals. This test also allows for confirmation of sterile males.

Turnaround Time
5-10 business days
Type of Sample

Species

Type of Test

Results Reported As
Test Result Androgen Insensitivity Syndrome

N/N

Normal female.

N/AR*

Female horse is a carrier of the AR variant.

N

Normal male.

AR*

Affected male. Genetic male horse will be insensitive to androgen and will be sterile.

*Results will be reported as AR1, AR2, AR3, AR4, or AR5 corresponding to the 5 known AIS variants.

References

Révay, T., Villagómez, D.A., Brewer, D., Chenier, T., & King, W.A. (2012). GTG mutation in the start codon of the androgen receptor gene in a family of horses with 64,XY disorder of sex development. Sexual Development, 6(1-3), 108-116. doi: 10.1159/000334049

Bolzon, C., Joonè, C.J., Schulman, M.L., Harper, C.K., Villagómez, D.A., King, W.A., & Révay, T. (2016). Missense Mutation in the Ligand-Binding Domain of the Horse Androgen Receptor Gene in a Thoroughbred Family with Inherited 64,XY (SRY+) Disorder of Sex Development. Sexual Development, 10(1), 37-44. doi: 10.1159/000444991

Welsford, G.E., Munk, R., Villagómez, D.A., Hyttel, P., King, W.A., & Revay, T. (2017). Androgen Insensitivity Syndrome in a Family of Warmblood Horses Caused by a 25-bp Deletion of the DNA-Binding Domain of the Androgen Receptor Gene. Sexual Development, 11(1), 40-45. doi: 10.1159/000455114

Villagomez, D.A.F., Welsford, E.G., King, W.A., & Revay, T. (2020). Androgen Receptor Gene Variants in New Cases of Equine Androgen Insensitivity Syndrome. Genes, 11(1), 78. doi: 10.3390/genes11010078