Androgen Insensitivity Syndrome (AIS)

Androgen Insensitivity Syndrome (AIS) is an inherited X-linked recessive disorder. In affected individuals, the development of the male reproductive organs is impaired. The normal karyotype of mares is 64, XX and that of stallions is 64, XY. The genetic information carried by the sex chromosomes controls the subsequent proper development of sex characteristics. The formation of testes and the subsequent production of testosterone lead to masculinization of the external genitalia. For masculinization to occur, the active involvement of androgens (male hormones) is required.

If androgens cannot perform their function properly – either because they are completely absent or because the tissues do not respond to them – the external genitalia gradually begin to differentiate as female. This physiological condition is referred to as male pseudohermaphroditism.

Mares may have a larger body frame, increased muscularity and a powerful neck. Their behaviour may resemble that of stallions. Pronounced vocalization in the presence of mares in oestrus, aggression towards other horses and absence of oestrus are common. The external genitalia appear female at first glance; the vagina is shortened, the cervix is not detectable and the uterus is absent. Abdominal ultrasound examination may reveal two testes near the normal location of the ovaries. The presence of testes explains normal to elevated testosterone levels.

In Warmblood horses, a 25-bp deletion was identified in exon 2 of the AR gene (g.52808634_52808658del). This is the third mutation associated with a diagnosis of AIS identified in horses and is therefore designated AR3. The deletion causes a frameshift and alters the amino acid sequence. The frameshift is presumed to result in the synthesis of a non-functional and truncated AR protein, subsequently causing adverse changes in the development of the male reproductive organs.

Resulting genotypes:

• X/X – healthy mare; does not carry the mutation in the AR gene and does not transmit it to her offspring.
• X/Y – healthy stallion; not affected by AIS.
• X(AR3)/X – heterozygous mare; has no clinical signs but carries the mutation and has a 50% probability of transmitting it to her offspring.
• X(AR3)/Y – affected stallion/mare; the external genitalia appear female, while the genotype is male; the mutation is not transmitted further – the individual is infertile.

Howden, Krista J. "Androgen insensitivity syndrome in a thoroughbred mare (64, XY—testicular feminization)." The Canadian Veterinary Journal 45.6 (2004): 501.

Welsford GE, Munk R, Villagómez DA, Hyttel P, King WA, Revay T. 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. Sex Dev. 2017;11(1):40-45. doi: 10.1159/000455114. Epub 2017 Feb 14. PMID: 28192783.