In other species: domestic cat , cattle , dog , pig

Possibly relevant human trait(s) and/or gene(s) (MIM number): 300068

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: Previously known as Testicular Feminisation Syndrome. Following the recommendations on nomenclature for disorders of sexual development (DSD) proposed by Lee et al. (Pediatrics 2006;118;e488; DOI: 10.1542/peds.2006-0738), this disorder is now classified as a type of XY DSD. This is an abnormality of sexual development in which affected individuals have an XY chromosomal constitution, undescended testes and female secondary sexual characteristics (including female external genitalia). Also, instead of normally developed Mullerian duct derivatives (Fallopian tubes, uterus, cervix, and upper protion of the vagina), they have under-developed Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle). In all species so far investigated, the inheritance is X-linked recessive. In humans and mice, this disorder is known to be due to a deficiency of an androgen receptor encoded by a gene on the X chromosome. The presence of a Y chromosome induces the undifferentiated embryonic gonads to develop as testes, but, in the absence of androgen receptor, the androgens produced by the testes cannot exert any effect. The result is that the embryo follows the "default" path of development, which is female.

Species-specific symbol: AIS

Markers: Figure 2 of Villagomez et al. (2020) provides a very clear summary of the five likely causal variants known to date.

Molecular basis: Révay et al. (2012) reported that this disorder in a family of American Quarter Horses is due to "a transition in the first nucleotide of the [androgen receptor] AR start codon (c.1A>G)", with the result that "a reduced amount of the functional AR is expressed during androgen-critical periods of development in the XY genetic male embryo, which alters its gonadal development and results in the observed phenotype". This is the first report of a mutation in the AR gene in domestic animals.

In a "Warmblood horse pedigree segregating AIS", Welsford et al. (2017) "provided evidences that a 25-bp deletion of the DNA-binding domain [of the AR gene] is causative" in this breed.

Villagomez et al. (2020) reported "two novel genetic variants for the AR-gene identified in a Tennessee Walking Horse and a Thoroughbred horse mare; each in individual clinical cases of horse AIS syndrome . . . c.183delT in Case #1 and c.2132C>T in Case #2".

Breeds: American Quarter Horse, Warmblood.

Associated gene: