GTG mutation in the start codon of the androgen receptor gene in a family of horses with 64,XY disorder of sex development.
Abstract: Genetic sex in mammals is determined by the sex chromosomal composition of the zygote. The X and Y chromosomes are responsible for numerous factors that must work in close concert for the proper development of a healthy sexual phenotype. The role of androgens in case of XY chromosomal constitution is crucial for normal male sex differentiation. The intracellular androgenic action is mediated by the androgen receptor (AR), and its impaired function leads to a myriad of syndromes with severe clinical consequences, most notably androgen insensitivity syndrome and prostate cancer. In this paper, we investigated the possibility that an alteration of the equine AR gene explains a recently described familial XY, SRY + disorder of sex development. We uncovered a transition in the first nucleotide of the AR start codon (c.1A>G). To our knowledge, this represents the first causative AR mutation described in domestic animals. It is also a rarely observed mutation in eukaryotes and is unique among the >750 entries of the human androgen receptor mutation database. In addition, we found another quiet missense mutation in exon 1 (c.322C>T). Transcription of AR was confirmed by RT-PCR amplification of several exons. Translation of the full-length AR protein from the initiating GTG start codon was confirmed by Western blot using N- and C-terminal-specific antibodies. Two smaller peptides (25 and 14 amino acids long) were identified from the middle of exon 1 and across exons 5 and 6 by mass spectrometry. Based upon our experimental data and the supporting literature, it appears that the AR is expressed as a full-length protein and in a functional form, and the observed phenotype is the result of reduced AR protein expression levels.
Copyright © 2011 S. Karger AG, Basel.
Publication Date: 2011-11-15 PubMed ID: 22095250DOI: 10.1159/000334049Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Case Reports
- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research study has discovered an unusual mutation in the androgen receptor (AR) gene in a family of horses experiencing a sex-development disorder. The findings indicate that this mutation is unique and the first of its kind found in domestic animals.
Androgen Receptor and Sexual Development
- The androgen receptor (AR) mediates the action of androgens, which are crucial for normal male sex differentiation in mammals.
- If the AR’s function is impaired, it can result in several severe syndromes with serious clinical implications such as androgen insensitivity syndrome and prostate cancer.
Understanding the Mutation
- The investigation in this paper was based on a familial XY disorder of sex development in horses – a situation where the sexual development does not match the chromosomal constitution (64, XY indicates a male genotype).
- Through their research, the scientists found a transition in the very first nucleotide of the AR start codon. This mutation is the first causative AR mutation in domestic animals reported to date.
- This mutation is rarely observed in eukaryotes (organisms whose cells have a nucleus enclosed within membranes) and is unique within the over 750 entries in the human androgen receptor mutation database.
- Additionally, another silent mutation was discovered in exon 1 (a region that includes the DNA sequences that code for the protein).
Consequences of the Mutation
- The transcription of AR was confirmed by RT-PCR amplification, and the translation of the complete AR protein was confirmed with Western blot.
- Two smaller peptides were identified, which suggest that the AR is expressed as a full-length protein and is functional.
- However, the phenotype or physical expression of the disorder seems to be the result of decreased AR protein expression levels. This implies that the mutation reduces AR protein production, directly impacting the normal process of sexual differentiation.
Cite This Article
APA
Révay T, Villagómez DA, Brewer D, Chenier T, King WA.
(2011).
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(1-3), 108-116.
https://doi.org/10.1159/000334049 Publication
Researcher Affiliations
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
MeSH Terms
- Amino Acid Sequence
- Animals
- Base Sequence
- Codon, Initiator / genetics
- DNA / blood
- Disorders of Sex Development / genetics
- Disorders of Sex Development / veterinary
- Female
- Horse Diseases / genetics
- Horses
- Male
- Molecular Sequence Data
- Mutation / genetics
- Mutation, Missense
- Point Mutation
- Receptors, Androgen / analysis
- Receptors, Androgen / chemistry
- Receptors, Androgen / genetics
- Sequence Alignment
- Sex Chromosomes / genetics
- Sex-Determining Region Y Protein / analysis
Citations
This article has been cited 7 times.- Bugno-Poniewierska M, Raudsepp T. Horse Clinical Cytogenetics: Recurrent Themes and Novel Findings.. Animals (Basel) 2021 Mar 16;11(3).
- Laseca N, Anaya G, Peña Z, Pirosanto Y, Molina A, Demyda Peyrás S. Impaired Reproductive Function in Equines: From Genetics to Genomics.. Animals (Basel) 2021 Feb 3;11(2).
- Ghosh S, Davis BW, Rosengren M, Jevit MJ, Castaneda C, Arnold C, Jaxheimer J, Love CC, Varner DD, Lindgren G, Wade CM, Raudsepp T. Characterization of A Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as A Risk Factor for Disorders of Sex Development and Reproduction.. Genes (Basel) 2020 Feb 27;11(3).
- Villagomez DAF, Welsford EG, King WA, Revay T. Androgen Receptor Gene Variants in New Cases of Equine Androgen Insensitivity Syndrome.. Genes (Basel) 2020 Jan 10;11(1).
- Ito H, Langenhorst T, Ogden R, Inoue-Murayama M. Androgen receptor gene polymorphism in zebra species.. Meta Gene 2015 Sep;5:120-3.
- Ghosh S, Qu Z, Das PJ, Fang E, Juras R, Cothran EG, McDonell S, Kenney DG, Lear TL, Adelson DL, Chowdhary BP, Raudsepp T. Copy number variation in the horse genome.. PLoS Genet 2014 Oct;10(10):e1004712.
- Trifonov VA, Dementyeva PV, Larkin DM, O'Brien PC, Perelman PL, Yang F, Ferguson-Smith MA, Graphodatsky AS. Transcription of a protein-coding gene on B chromosomes of the Siberian roe deer (Capreolus pygargus).. BMC Biol 2013 Aug 6;11:90.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
