Genetics of Steroid Receptors and Their Disorders

Pinsky, Leonard; Kaufman, Morris

doi:10.1007/978-1-4757-0620-8_5

Cited by 22 publications

(8 citation statements)

References 504 publications

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“…*RF 4-7* Known single gene defects include Kartagener's syndrome,8 partial deficiency of androgen receptors,9 and possibly oligochiasmate maturation arrest 10. Subfertility in men is also associated with medical conditions such as pituitary deficiency or cryptorchidism, which may themselves have a genetic component.…”

Section: Introductionmentioning

confidence: 99%

Case-control study of whether subfertility in men is familial

Lilford

Jones

Bishop

et al. 1994

BMJ

140

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Objective-To test the hypothesis that subfertility in men is familial and to examine the distribution of subfertility within families for consistency with a genetic cause.Design-Case-control study and segregation analysis.Setting-Two teaching hospitals in Leeds. Subjects-Cases (probands) were men with an abnormal sperm count who attended a subfertility clinic and whose partners had no major factor contravening fertility. Controls were fathers of two or more childen recruited through vasectomy clinics or a maternity department.Main outcome measures-The incidence of involuntary childlessness among brothers with partners and among sisters and second and third degree male relatives. When possible clinical and laboratory details were obtained from involuntarily childless brothers.Results-Seventeen of the 148 (11.5a/.) brothers of probands but none ofthe 169 brothers ofcontrols had sought medical advice for childlessness (P< 0.0005).Four probands had more than one involuntarily childless brother. There were six further brothers whose childlessness was thought to be involuntary bringing the total prevalence of subfertility among brothers of probands to 16%. Segregation analysis was consistent with an autosomal recessive mode of inheritance accounting for 60"/! of subfertility in men. Seventeen ofthe 346 (4.9%/6) uncles ofprobands and 10 of420 (2.8"/!) uncles ofcontrols were reported to be involuntarily childless (P=0.09), but there was no difference in childlessness among sisters. In three families sperm counts from "affected" brothers confirmed the diagnosis and showed considerable similarities within but not between families.Conclusion-Subfertility in men has a familial component, and the observations are consistent with an autosomal recessive mode of inheritance in over half the cases. Several different genes are probably involved.Insttute ofEpidemiology

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Section: Introductionmentioning

confidence: 99%

Case-control study of whether subfertility in men is familial

Lilford

Jones

Bishop

et al. 1994

BMJ

140

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“…The androgen receptor (AR) is a transcription-regulating protein that plays a pivotal role in the programming of male sexual differentiation and development. Absence or mutation of the X-chromosome-located AR gene can lead to complete androgen-insensitivity, and the affected 46,XY individual displays the external phenotype of a female [1][2][3][4][5][6][7]. Mutations in AR are also thought to be involved in less severe forms of aberrant male sexual development.…”

Section: Introductionmentioning

confidence: 99%

The mouse androgen receptor. Functional analysis of the protein and characterization of the gene

Faber

King

Rooij

et al. 1991

Biochemical Journal

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Screening a mouse genomic DNA library with human androgen-receptor (hAR) cDNA probes resulted in the isolation and characterization of eight genomic fragments that contain the eight exons of the mouse androgen-receptor (mAR) gene. On the basis of similarity to the hAR gene, the nucleotide sequences of the protein-coding parts of the exons as well as the sequences of the intron/exon boundaries were determined. An open reading frame (ORF) of 2697 nucleotides, which can encode an 899-amino-acid protein, could be predicted. The structure of the mAR ORF was confirmed by sequence analysis of mAR cDNA fragments, which were obtained by PCR amplification of mouse testis cDNA, using mAR specific primers. A eukaryotic mAR expression vector was constructed and mAR was transiently expressed in COS-1 cells. The expressed protein was shown by Western blotting to be identical in size with the native mAR. Co-transfection of HeLa cells with the mAR expression plasmid and an androgen-responsive chloramphenicol acetyltransferase (CAT) reporter-gene construct showed mAR to be able to trans-activate the androgen-responsive promoter in a ligand-dependent manner. Transcription-initiation sites of the mAR gene were identified by S1-nuclease protection experiments, and the functional activity of the promoter region was determined by transient expression of mAR promoter-CAT-reporter-gene constructs in HeLa cells. Structural analysis revealed the promoter of the mAR gene to be devoid of TATA/CCAAT elements. In addition, the promoter region is not remarkably (G + C)-rich. Potential promoter elements consist of a consensus Sp1 binding sequence and a homopurine stretch. The polyadenylation sites of mAR mRNA were identified by sequence similarity to the corresponding sites in the hAR mRNA.

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“…A number of aberrations of male sexual differentiation and development are associated with defects in the androgen receptor protein (1,14). These defects can vary from a complete female phenotype in a 46,XY individual [complete androgen insensitivity syndrome (AIS)] to partial disorders of male sexual differentiation (partial AIS).…”

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confidence: 99%

“…Both the complete and the partial form of AIS can manifest at the protein level in either the absence or the presence of androgen binding. In the latter case, qualitative defects in androgen binding have been reported (1,14). Therefore, naturally occurring mutations in the androgen receptor are a potentially interesting source for the investigation of receptor structure-function relationships.…”

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confidence: 99%

Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity.

Ris-Stalpers

Kuiper

Faber

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symptoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. We report a G -a' T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46,XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4, which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein -5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.

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Genetics of Steroid Receptors and Their Disorders

Cited by 22 publications

References 504 publications

Case-control study of whether subfertility in men is familial

Case-control study of whether subfertility in men is familial

The mouse androgen receptor. Functional analysis of the protein and characterization of the gene

Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity.

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