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In-vitro Characterization of Androgen Receptor Mutations Associated with Complete Androgen Insensitivity Syndrome Reveals Distinct Functional Deficits
- Source :
- Sexual Development. 2:73-83
- Publication Year :
- 2008
- Publisher :
- S. Karger AG, 2008.
-
Abstract
- Adequate androgen receptor (AR) function is crucial for male sex development and maintenance of secondary male characteristics. Mutations in the AR lead to androgen insensitivity syndrome (AIS) characterized by an end-organ resistance to androgens. The clinical appearance of individuals with 46,XY karyotype and an AR mutation varies widely from normal male to the ultimate completely female phenotype of complete androgen insensitivity syndrome (CAIS). We have analyzed the androgen receptor missense mutations P723S, P904S, and H917R, clinically associated with CAIS, which were described to have a normal maximum androgen binding (Bmax) but elevated equilibrium dissociation constants (Kd’s) and compared their properties with the F916X deletion mutant, leading to the loss of the last four amino acids of the AR. Functional analysis allowed a quantitative and qualitative discrimination of these mutants in transactivation, amino-terminal/carboxy-terminal (N/C)-interaction, and coactivation capacity, varying widely with each distinct mutation. We conclude that mutations in the AR have to be characterized meticulously, not only to prove any quantitative functional deficit as a proof of consequence, but also to gain knowledge on qualitative functional properties. This is necessary as a possible link to genotype-phenotype correlation in AIS, but also with respect to medical decision making in CAIS.
- Subjects :
- Adult
Male
Transcriptional Activation
Embryology
medicine.medical_specialty
Transcription, Genetic
Endocrinology, Diabetes and Metabolism
CHO Cells
Biology
urologic and male genital diseases
Cricetulus
Complete androgen insensitivity syndrome
Cricetinae
Internal medicine
medicine
Animals
Humans
Genetic Predisposition to Disease
Child
Androgen-Insensitivity Syndrome
medicine.disease
In vitro
Protein Structure, Tertiary
Androgen receptor
Endocrinology
Receptors, Androgen
Mutation
Female
Mutant Proteins
Androgen insensitivity syndrome
Developmental Biology
Subjects
Details
- ISSN :
- 16615433 and 16615425
- Volume :
- 2
- Database :
- OpenAIRE
- Journal :
- Sexual Development
- Accession number :
- edsair.doi.dedup.....67d2455663d309cb292b2e7d4d2b122a