Comparison of the molecular consequences of different mutations at residue 754 and 690 of the androgen receptor (AR) and androgen insensitivity syndrome (AIS) phenotype

Tadokoro, Rieko; Bunch, Trevor; Schwabe, John W. R.; Hughes, Ieuan A.; Murphy, Jane

doi:10.1111/j.1365-2265.2008.03462.x

Cited by 20 publications

(14 citation statements)

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“…A normal Kd value can be expected for mutants p.Cys177Gly and p.Arg609Met. The Kd value for the p.Asp691del mutant was published previously [Tadokoro et al, 2009]. All mutants with some transcriptional activation displayed Kd values that were significantly higher than that of the wild type receptor, indicat- ing a decreased affinity for mibolerone, although the Kd value did not directly correlate with transcriptional activity in a quantitative sense.…”

Section: Hormone-binding Characteristicsmentioning

confidence: 99%

“…Three variants have been reported previously: p.Asp691del in a CAIS patient of whom the mother was a carrier; p.Leu723Phe in a female PAIS patient and p.Ala766Ser in a male PAIS patient of whom the mother was also carrier [Hiort et al, 1996;Chávez et al, 2001;Tadokoro et al, 2009]. Further information on phenotypes, family history and gender identities are summarized in table 1 .…”

Section: Mutation Analysismentioning

confidence: 99%

“…4 D, F and J, respectively). In these mutants, the results reflected the absence of ligand activation, indirectly resulting in the inability to stably bind to DNA, where- Tadokoro et al, 2009. as the p.Arg609Met substitution still enabled ligand binding and nuclear translocation but directly inhibited stable DNA binding. These properties were in accordance with the lack of transcriptional activation of the 4 mutants.…”

Section: In Comparison With Wt Ar (Showing Transient Immobilizations)mentioning

confidence: 99%

“…Although several reports have established the pathogenic nature of AR variants found in AIS individuals with different functional assays [Umar et al, 2005;Wong et al, 2008;Elfferich et al, 2009;Tadokoro et al, 2009], prediction of phenotypes on the basis of detected mutations can be difficult. To optimize molecular diagnosis, an extensive functional analysis of AR variants is desired.…”

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confidence: 99%

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Variable Loss of Functional Activities of Androgen Receptor Mutants in Patients with Androgen Insensitivity Syndrome

Elfferich¹,

Royen²,

Wijngaart³

et al. 2013

Sex Dev

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Androgen receptor (AR) mutations in androgen insensitivity syndrome (AIS) are associated with a variety of clinical phenotypes. The aim of the present study was to compare the molecular properties and potential pathogenic nature of 8 novel and 3 recurrent AR variants with a broad variety of functional assays. Eleven AR variants (p.Cys177Gly, p.Arg609Met, p.Asp691del, p.Leu701Phe, p.Leu723Phe, p.Ser741Tyr, p.Ala766Ser, p.Arg775Leu, p.Phe814Cys, p.Lys913X, p.Ile915Thr) were analyzed for hormone binding, transcriptional activation, cofactor binding, translocation to the nucleus, nuclear dynamics, and structural conformation. Ligand-binding domain variants with low to intermediate transcriptional activation displayed aberrant Kd values for hormone binding and decreased nuclear translocation. Transcriptional activation data, FxxFF-like peptide binding and DNA binding correlated well for all variants, except for p.Arg609Met, p.Leu723Phe and p.Arg775Leu, which displayed a relatively higher peptide binding activity. Variants p.Cys177Gly, p.Asp691del, p.Ala766Ser, p.Phe814Cys, and p.Ile915Thr had intermediate or wild type values in all assays and showed a predominantly nuclear localization in living cells. All transcriptionally inactive variants (p.Arg609Met, p.Leu701Phe, p.Ser741Tyr, p.Arg775Leu, p.Lys913X) were unable to bind to DNA and were associated with complete AIS. Three variants (p.Asp691del, p.Arg775Leu, p.Ile915Thr) still displayed significant functional activities in in vitro assays, although the clinical phenotype was associated with complete AIS. The data show that molecular phenotyping based on 5 different functional assays matched in most (70%) but not all cases.

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Section: Hormone-binding Characteristicsmentioning

confidence: 99%

Section: Mutation Analysismentioning

confidence: 99%

Section: In Comparison With Wt Ar (Showing Transient Immobilizations)mentioning

confidence: 99%

mentioning

confidence: 99%

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Variable Loss of Functional Activities of Androgen Receptor Mutants in Patients with Androgen Insensitivity Syndrome

Elfferich¹,

Royen²,

Wijngaart³

et al. 2013

Sex Dev

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“…46,47 Androgen receptor function and mutations correlate somewhat in utero; this association is shown by the degree of external genital masculinisation. 48 Transcriptional activity is generally absent or severely impaired on a physiological androgen basis in studies of androgen-receptor mutations associated with a phenotype of complete androgen insensitivity syndrome. The spontaneous mutation rate in complete androgen insensitivity syndrome is about 30%-a fi nding consistent with other X-linked recessive disorders such as haemophilia (due to factor VIII defi ciency) and Duchenne muscular dystrophy.…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Androgen Insensitivity Syndrome (AIS)

安藤紀子¹,

平吹知雄²,

沢井かおり³

et al.

Encyclopedia of Cancer

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Androgen insensitivity syndrome in its complete form is a disorder of hormone resistance characterised by a female phenotype in an individual with an XY karyotype and testes producing age-appropriate normal concen trations of androgens. Pathogenesis is the result of mutations in the X-linked androgen receptor gene, which encodes for the ligand-activated androgen receptor-a transcription factor and member of the nuclear receptor superfamily. This Seminar describes the clinical manifestations of androgen insensitivity syndrome from infancy to adulthood, reviews the mechanism of androgen action, and shows examples of how mutations of the androgen receptor gene cause the syndrome. Management of androgen insensitivity syndrome should be undertaken by a multidisciplinary team and include gonadectomy to avoid gonad tumours in later life, appropriate sex-hormone replacement at puberty and beyond, and an emphasis on openness in disclosure.

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Androgen Insensitivity

Brinkmann¹

2010

Encyclopedia of Life Sciences

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Androgen insensitivity is an X‐linked disorder of defective or absent virilisation in 46, XY individuals due to complete or partial resistance to androgens in androgen‐dependent tissues and organs. The syndrome is part of a scala of disorders of sex development (DSD). The molecular cause of the syndrome is mutations in the androgen receptor gene (locus: Xq11.2–12), resulting either in absence of an androgen receptor protein or in production of a mutant androgen receptor protein with partial or complete loss of its activity. Androgen insensitivity displays a broad phenotypic and genotypic spectrum. The phenotype can vary from a complete form (CAIS, complete androgen insensitivity syndrome), partial form (PAIS, partial androgen insensitivity syndrome) to a mild form (MAIS, mild androgen insensitivity syndrome). More than 400 different mutations in the androgen receptor gene have been reported. The majority of mutations are single‐base substitutions. However, deletions (1–6 base pairs), partial or complete gene deletions (>10 base pairs), insertions or duplications are also found. Mutations are compiled in the androgen receptor database ( www.mcgill.ca/androgendb ). Key Concepts: Androgens and the androgen receptor are indispensable for expression of the male phenotype. The androgen receptor is a ligand‐dependent transcription factor and belongs to the family of nuclear receptors. Despite two different ligands (testosterone and 5α‐dihydrotestosterone), only one androgen receptor cDNA has been identified and cloned. A highly polymorphic (CAG) n ‐CAA repeat, encoding a polyglutamine stretch, in exon 1 of the androgen receptor gene is used for identification of X‐chromosomes for carrier detection in pedigree analyses. Variations in the polyglutamine stretch modulate androgen receptor transcriptional activity. End‐organ resistance to androgens has been designated as androgen insensitivity syndrome (AIS) and is distinct from other XY disorders of sex development. Defects in the androgen receptor gene can prevent normal development of both internal and external male structures in 46, XY individuals. End‐organ resistance to androgens is X‐linked and only 46, XY individuals are affected. AR gene mutations are transmitted in an X‐linked manner, but in 30% of the cases, mutations arise de novo . Androgen insensitivity can be routinely analysed and differential diagnosis is possible with other syndromes presenting with almost similar phenotypes.

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Comparison of the molecular consequences of different mutations at residue 754 and 690 of the androgen receptor (AR) and androgen insensitivity syndrome (AIS) phenotype

Cited by 20 publications

References 40 publications

Variable Loss of Functional Activities of Androgen Receptor Mutants in Patients with Androgen Insensitivity Syndrome

Variable Loss of Functional Activities of Androgen Receptor Mutants in Patients with Androgen Insensitivity Syndrome

Androgen Insensitivity Syndrome (AIS)

Androgen Insensitivity

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