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

Abstract

Disorders of sex development (DSD) have long been documented in domestic animal species including horses. However, there is only a single report of an androgen receptor (AR) mutation causative of such a DSD syndrome in a horse pedigree. Here, we present a new familial AR mutation in horses. A missense mutation (c.2042G>C) at AR exon 4 explains the segregation of the DSD in a Thoroughbred horse pedigree. The mutation, expected to affect the ligand-binding domain of the AR protein, led to complete androgen insensitivity of 64,XY SRY+, testicular DSD individuals. Additionally, the design of a PCR-RFLP technique provided an accurate molecular test for the identification of horses carrying the mutation.

Disorders of sex development in cats with different complements of sex chromosomes

“…It is known from human medicine that a large proportion of XY DSD has unknown background; however, numerous candidate genes with potentially causative mutations have been described (Alhomaidah, McGowan, & Ahmed, 2017;Eggers et al, 2016;Flück & Pandey, 2014). In domestic mammals, causative mutations in XY DSD animals were only found in the Mullerian inhibiting substance type-2 receptor gene (MISR2), which is responsible for persistent Mullerian duct syndrome in Miniature Schnauzer dogs (Wu et al, 2009) and in the androgen receptor gene (AR), where it causes androgen insensitivity syndrome in horses (Bolzon et al, 2016;Révay, Villagómez, Brewer, Chenier, & King, 2012;Welsford et al, 2017). In our study, the decreased number of Leydig cells and low testosterone level led us to analyse, for the first time, the coding sequence of two feline candidate genes (HSD3B2 and HSD17B3) that encode enzymes involved in the synthesis of androgens.…”

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

“…Comparison of the sequences of the pedigree members to one another and to the horse AR reference sequence identified 2 variable positions: a substitution and a deletion. When compared to the reference C allele, the T allele of the previously described neutral exon 1 c.322C>T substitution [Révay et al, 2012;Bolzon et al, 2016] was observed in all 4 sequenced animals (DSD-M1, DSD-M2, N-M1, N-S1). Additionally, a 25-bp deletion in exon 2 (c.1630_1654del) was discovered, deleting 8 codons from the end of exon 2 ( Fig.…”

“…however, the molecular link between mutations of the AR gene and clinical characteristics of AIS were established in only 2 previous reports [Révay et al, 2012;Bolzon et al, 2016].…”

“…Quantitative polymerase chain reaction (qPCR) was used to determine the presence of X and Y chromosomes in the 7 related offspring (DSD-M1, DSD-M2, DSD-M3, DSD-M4, N-M1, N-S1, N-S2) and controls for both sexes using the method previously described [Bolzon et al, 2016]. Five Y chromosome genes ( SRY, USP9Y, EIF1AY, TSPY, ZFY ) and a single copy X chromosomal gene ( AR ) were tested.…”

“…While male pseudohermaphroditism or AIS has been reported in several domestic species including dogs, cats, horses, and cattle [Howden, 2004;Lyle, 2007], detailed molecular investigations in horses are restricted to 2 studies. A missense mutation (c.2042G>C) was identified in members of a Thoroughbred family and presumed to result in the substitution of a very important tryptophan residue with serine in the AR LBD [Bolzon et al, 2016], and a rare start codon mutation (c.1A>G) in the American Quarter horse breed resulted in complete androgen insensitivity for 3 members of the horse family [Révay et al, 2012]. Both of these exonic mutations segregated in the pedigree according to the AIS phenotype.…”