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A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat.
Open accessAbstract
The complete form of androgen insensitivity is an inherited X-linked syndrome in which genetic males fail to undergo masculinization in utero due to defective functioning of the androgen receptor (AR). The molecular basis of androgen insensitivity was investigated in the testicular feminized (Tfm) rat with this syndrome. AR mRNA size and amount, as well as nuclear AR protein revealed by immunocytochemistry, suggested normal expression of the AR gene in the Tfm rat. Sequence analysis of the AR coding region from Tfm and wild-type littermate male rats revealed a single transition mutation, guanine to adenine, within exon E, changing arginine 734 to glutamine within the steroid-binding domain of the AR. This arginine is highly conserved among the family of nuclear receptors and may be part of a phosphorylation recognition site. A recreated mutant AR (Arg734----Gln) expressed in COS cells had only 10-15% of the androgen-binding capacity of wild-type AR; the reduced androgen-binding capacity was similar to that of AR in tissue extracts of the Tfm rat. Stimulation of transcriptional activity by the recreated mutant AR was reduced relative to wild-type AR in cotransfection assays in CV1 cells using as reporter plasmid the mouse mammary tumor virus promoter linked to the chloramphenicol acetyltransferase gene. Thus, arginine 734 appears essential for normal AR function both in androgen binding and transcriptional activation. Absence of these functions results in androgen insensitivit…
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“In the rat (Stanley, Gumbreck, Allison, & Easley, 1973), the tfm is a consequence of a point mutation in the androgen receptor gene corresponding to the steroid-binding domain (Yarbrough et al., 1990) resulting in largely nonfunctional androgen receptors.”
From Play fighting in androgen-insensitivetfm rats: Evidence that androgen receptors are necessary for the development of adult playful attack and defense (2006) · cites this paper as Yarbrough et al., 1990
In the citing paper
“Given that in the tfm mutation, it is the androgen receptor, not the estrogen receptor that is nonfunctional (Yarbrough et al., 1990)”
From Play fighting in androgen-insensitivetfm rats: Evidence that androgen receptors are necessary for the development of adult playful attack and defense (2006) · cites this paper as Yarbrough et al., 1990
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“These rats embryologically develop testes and secrete testosterone prenatally; however, because they express dysfunctional AR protein, these rats develop a wholly feminine exterior phenotype, including a clitoris and defective vagina, rather than a penis and prostate [10, 11, 13].”
BackgroundBACKGROUND REVIEW DOCUMENT ON THE RODENT
Bioassay, H. (2008)
Levalle, O., Endocrinología, D., & Durand, C. G. (2015)
Myocyte Androgen Receptor Modulates Body Composition and Metabolic Parameters
Fernando, S. M. (2010) · TSpace (University of Toronto)
Effects of Androgen Receptor Overexpression on Select Sexually Dimorphic Neural Structures
Ramzan, F. (2014) · TSpace (University of Toronto)
Adenyo, C., KAYANG, B. B., & Inoue‐Murayama, M. (2018) · Institutional Repositories DataBase (IRDB) · doi:10.14989/236669
“…reaction (PCR) primers, androgen receptor exon one sequences of rat, mouse and guinea pig containing the CAG repeats with accession numbers J05454 (Yarbrough et al., 1990), X59592 (Faber et al., 1991) and AJ893531 (Poux et al., 2005) respectively were aligned with ClustalW (Thompson et al., 1994)…”
MethodMetabolic, Traumatic, and Miscellaneous Diseases
King, W. W., & Drake, M. T. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-814338-4.00016-7
Rosenfield, R. L. (2005) · Experimental Dermatology · doi:10.1111/j.0906-6705.2005.0285d.x
Androgenrezeptor in Gesundheit und Krankheit
Hohl, A., & Marcelli, M. (2024) · Springer eBooks · doi:10.1007/978-3-031-65245-5_2
Syndromes d’insensibilite aux androgenes: Aspects moleculaires
Sultan, C., Lobaccaro, J. A., Lumbroso, S., Belon, C., & Audran, F. (1992) · Andrologie · doi:10.1007/bf03034686
Karameh, N. (2018) · theses.fr (ABES) · doi:10.70675/b70b7c03z8de8z4ee0z9848z381e95568515
Rôle de NR5A1 dans le destin des cellules de Sertoli fœtales chez la souris
Souali‐Crespo, S. (2021) · theses.fr (ABES) · doi:10.70675/0221a4d3zfa87z4360zb881z4bea8d058b3e
Metadata
- Authors
- Yarbrough, W. G., Quarmby, V. E., Simental, J. A., Joseph, D. R., Sar, M., Lubahn, D. B., Olsen, K. L., French, F. S., & Wilson, E. M.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1990-05
- Volume
- 265
- Issue
- 15
- Pages
- 8893-8900
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1565230790
- Cited by
- 199
- References
- 59
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 4 · 2015: 8 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion, cc-by)
- UNC Libraries
- Funders
- Andrew W. Mellon Foundation
- National Institutes of Health (5p30hd018968-12)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P-30 HD18968, HD-16910, HD04466)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- androgen receptor, androgen insensitivity syndrome, single-base mutations, steroid-binding domain, androgen binding, transcriptional activation, male reproductive development, X-linked disorders, rat model
- MeSH terms
- Amino Acid Sequence, Androgens, Animals, Base Sequence, Cell Line, DNA, Feminization, Gene Amplification, Humans, Male, Molecular Sequence Data, Mutation, Rats, Mutant Strains, Receptors, Androgen, RNA, Messenger, Sequence Homology, Nucleic Acid, Transfection, X Chromosome, Restriction Mapping, Rats
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