OMIA:000991-9796 : Androgen insensitivity syndrome (AIS) in Equus caballus
In other species: domestic cat , taurine cattle , dog , pig
Categories: Reproductive system phene
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 300068 (trait) , 313700 (gene)
Links to MONDO diseases: No links.
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: Quarter Horse (Horse) (VBO_0001057), Tennessee Walking Horse (Horse) (VBO_0001081), Thoroughbred (Horse) (VBO_0001083).
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|AR||androgen receptor||Equus caballus||X||NC_009175.3 (52728703..52884282)||AR||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|436||Quarter Horse (Horse)||Androgen insensitivity syndrome (AIS)||AR||regulatory||Naturally occurring variant||EquCab3.0||X||g.52728703A>G||c.1A>G||NM_001163891.1; NP_001157363.1; mutation in start codon||2012||22095250||The genomic position in EquCab3.0 was provided by Ceara Mulvey, working under the guidance of Professor Ernie Bailey in April 2022|
|1143||Tennessee Walking Horse (Horse)||Androgen insensitivity syndrome (AIS)||AR||deletion, small (<=20)||Naturally occurring variant||EquCab3.0||X||g.52728885del||c.183del||p.(R63Gfs)||NM_001163891.1; NP_001157363.1; published as c.183delT and p.(Ser61fs); c. and p. information in the table has been updated to HGVS nomenclature||2020||31936796||The genomic position in EquCab3.0 was provided by Ceara Mulvey, working under the guidance of Professor Ernie Bailey in April 2022|
|783||Androgen insensitivity syndrome||AR||deletion, gross (>20)||Naturally occurring variant||EquCab3.0||X||g.52808634_52808658del||c.1630_1654del||NM_001163891.1; NP_001157363.1; the deletion is predicted to create a frameshift: "resulting in altered amino acid composition from p.543Lys and a premature stop codon 44 amino acid residues downstream in exon 3"||2017||28192783|
|786||Thoroughbred (Horse)||Androgen insensitivity syndrome||AR||missense||Naturally occurring variant||EquCab3.0||X||g.52872393G>C||c.2042G>C||p.(W681S)||NM_001163891.1; NP_001157363.1||2016||27073903||The genomic position in EquCab3.0 was provided by Ceara Mulvey, working under the guidance of Professor Ernie Bailey in April 2022; p. coordinates obtained from Villagomez et al. (2019)|
|1144||Thoroughbred (Horse)||Androgen insensitivity syndrome (AIS)||AR||missense||Naturally occurring variant||EquCab3.0||X||g.52878093C>T||c.2132C>T||p.(A711V)||NM_001163891.1; NP_001157363.1||2020||31936796|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2020||Villagomez, D.A.F., Welsford, E.G., King, W.A., Revay, T. :|
|Androgen receptor gene variants in new vases of equine androgen insensitivity syndrome. Genes (Basel) 11:78, 2020. Pubmed reference: 31936796 . DOI: 10.3390/genes11010078.|
|2017||Welsford, G.E., Munk, R., Villagómez, D.A., Hyttel, P., King, W.A., 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 11:40-45, 2017. Pubmed reference: 28192783 . DOI: 10.1159/000455114.|
|2016||Bolzon, C., Joonè, C.J., Schulman, M.L., Harper, C.K., Villagómez, D.A., King, W.A., Révay, T. :|
|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. Sex Dev 10:37-44, 2016. Pubmed reference: 27073903 . DOI: 10.1159/000444991.|
|2012||Pujar, S., Meyers-Wallen, V. :|
|Sequence variations in equine candidate genes for XX and XY inherited disorders of sexual development. Reprod Domest Anim 47:827-834, 2012. Pubmed reference: 22239239 . DOI: 10.1111/j.1439-0531.2011.01976.x.|
|Révay, T., Villagómez, D.A., Brewer, D., Chenier, T., King, W.A. :|
|GTG mutation in the start codon of the androgen receptor gene in a family of horses with 64,XY disorder of sex development. Sex Dev 6:108-16, 2012. Pubmed reference: 22095250 . DOI: 10.1159/000334049.|
|2011||Villagómez, D.A., Lear, T.L., Chenier, T., Lee, S., McGee, R.B., Cahill, J., Foster, R.A., Reyes, E., St John, E., King, W.A. :|
|Equine disorders of sexual development in 17 mares including XX, SRY-negative, XY, SRY-negative and XY, SRY-positive genotypes. Sex Dev 5:16-25, 2011. Pubmed reference: 21196712 . DOI: 10.1159/000322811.|
|2005||Switonski, M., Chmurzynska, A., Szczerbal, I., Lipczynski, A., Yang, F., Nowicka-Posluszna, A. :|
|Sex reversal syndrome (64,XY; SRY-positive) in a mare demonstrating masculine behaviour. J Anim Breed Genet 122 Suppl 1:60-3, 2005. Pubmed reference: 16130458 .|
|2004||Howden, K.J. :|
|Androgen insensitivity syndrome in a thoroughbred mare (64, XY--testicular feminization). Can Vet J 45:501-3, 2004. Pubmed reference: 15283519 .|
|1992||Crabbe, B.G., Freeman, D.A., Grant, B.D., Kennedy, P., Whitlatch, L., Macrae, K. :|
|Testicular feminization syndrome in a mare. Journal of the American Veterinary Medical Association 200:1689-1691, 1992. Pubmed reference: 1624347 .|
|1986||Enbergs, H., Schulte-Beckhausen, W. :|
|[Sex chromosome anomalies in mares and cytogenetic investigations on mares with severe fertility disturbances] Zuchthygiene 21:105-114, 1986.|
|1976||Kieffer, N.M. :|
|Male pseudohermaphroditism of the testicular feminizing type in a horse. Equine Vet J 8:38-41, 1976. Pubmed reference: 943286 .|
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