Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene

Yong, Eu Leong; Ng, S.C.; Roy, A.C.; Guo, Yun; Ratnam, S. S.

doi:10.1016/s0140-6736(94)92385-x

Cited by 87 publications

(44 citation statements)

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“…Apart from one successful experience with mesterolone (1a-methylandrostan-17β-ol-3-one) in promoting spermatogenesis and fertility twice in a man with MAIS, 98 experience with long-term natural androgen pharmacotherapy is meager and its value unclear. 44,[99][100][101] …”

Section: Maismentioning

confidence: 99%

Androgen insensitivity syndrome: clinical features and molecular defects

et al. 2008

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The end-organ resistance to androgens has been designated as Androgen Insensitivity Syndrome (AIS), an X-linked disorder caused by mutations in the Androgen Receptor (AR) gene. It is generally accepted that defects in the AR gene prevent the normal development of both internal and external genital structures in 46,XY individuals, causing a variety of phenotypes ranging from male infertility to completely normal female external genitalia. Precise diagnosis requires clinical, hormonal and molecular investigation and is of great importance for appropriate gender assignment and management in general. The complexity of phenotypic presentation of AIS with genotype-phenotype variability of identical mutations complicates both the diagnostic procedure and genetic counseling of the affected families. More than 400 different AR gene mutations have thus far been reported but the receptor structure-function relationship and its phenotypic outcome is not yet fully understood. This review focuses on the clinical features and molecular pathophysiology of AIS and explores the relationship of the molecular defects in the AR gene to their clinical expression.

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Section: Maismentioning

confidence: 99%

Androgen insensitivity syndrome: clinical features and molecular defects

et al. 2008

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“…found in an individual with PAIS (Yong et al, 1994). Other data indicated that N727 could influence NC-TDI and TIF2 co-activation (Lim et al, 2000).…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 95%

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Wong

Hoogerbrugge

Pang

et al. 2008

Molecular and Cellular Endocrinology

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A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH 2 -/COOH-terminal domain interaction and TIF2 co-activation, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abbreviations: aa, amino acid; AD, activation domain; AF2, activation function 2; DHT, 5-dihydrotestosterone; DSD, disorders of sex development; GFP, green fluorescent protein; GSF, genital skin fibroblast; LBD, ligand binding domain; LBP, ligand binding pocket; N-CoR, nuclear receptor co-repressor; NC-TDI, NH 2 -/COOH-terminal domain interaction; NTD, N-terminal transactivation domain; T, testosterone; TIF2, transcriptional intermediary factor 2; wt, wild-type. However, an at least two-fold higher NH 2 -/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range.Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.

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“…The normal number of CAG repeats is 11-36, whereas the mutant gene has up to 68 repeats. Presumably SBMA is caused by a gain-of-function mutation because severe testicular feminization patients where AR is fully inactivated do not have motor neuron disease (3,4). However, male patients with SBMA exhibit some symptoms of partial androgen insensitivity, including gynecomastia, small testicles, and feminization, suggesting some impairment of AR function (5).…”

mentioning

confidence: 99%

Kennedy's Disease

LaFevre-Bernt

Ellerby

2003

Journal of Biological Chemistry

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X-linked spinal and bulbar muscular atrophy is a degenerative disease affecting motor neurons that is caused by polyglutamine (polyQ) expansion within the androgen receptor (AR). The polyQ-expanded form of AR is cytotoxic to cells, and proteolytic cleavage enhances cell death. The intracellular signaling pathways activated and/or required for cell death induced by the expanded form of AR (AR112) are unknown. We found that AR regulates mitogen-activated protein kinase (MAP kinase) pathways and, therefore, hypothesized that these pathway(s) may be required for AR112-induced cell death. The polyQ expansion in AR activates three MAP kinase pathways, causing increasing levels of phosphorylation of p44/42, p38, and SAPK/JNK MAP kinase. Inhibitors of either the JNK or p38 pathways had no effect on AR112-induced cell death, suggesting they are not required for polyQ-induced cell death. Strikingly, the MEK1/2 inhibitor, U0126, which selectively inhibits the p44/42 MAP kinase pathway, reduces AR112-stimulated cell death. The inhibition of the MEK1/2 pathway correlates directly with a change in phosphorylation state of the androgen receptor. Mutation of the MAP kinase consensus phosphorylation site in AR at serine 514 blocked AR-induced cell death and the generation of caspase-3-derived cleavage products. We propose a mechanism by which phosphorylation at serine 514 of AR enhances the ability of caspase-3 to cleave AR and generate cytotoxic polyQ fragments.Spinal and bulbar muscular atrophy (SBMA), 1 or Kennedy's disease, is an X-linked autosomal dominant degenerative disease of the motor neurons, characterized by progressive muscle atrophy and weakness in male patients (1). The disease is caused by a polyglutamine (polyQ) tract expansion within the transcriptional activation domain of androgen receptor (AR) (2). The normal number of CAG repeats is 11-36, whereas the mutant gene has up to 68 repeats. Presumably SBMA is caused by a gain-of-function mutation because severe testicular feminization patients where AR is fully inactivated do not have motor neuron disease (3, 4). However, male patients with SBMA exhibit some symptoms of partial androgen insensitivity, including gynecomastia, small testicles, and feminization, suggesting some impairment of AR function (5). SBMA is one of a growing number of polyQ-repeat diseases, including Huntington's disease and the spinocerebellar ataxias, that are characterized by the death of specific neuronal subsets (6). It is particularly attractive to study the effect of a polyQ expansion in the context of AR because, unlike the other polyQ disease proteins, it has a well characterized function. AR is a transcription factor and a member of a large family of steroid hormone receptors (7,8).Almost all the polyQ proteins identified to date are substrates for cell death proteases or caspases (9 -13). The expanded form of AR is toxic to cells in both cell culture systems and transgenic animal models (9,14). Recent studies both in Drosophila and in transgenic mouse models of SBMA, expressing fu...

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Pregnancy after hormonal correction of severe spermatogenic defect due to mutation in androgen receptor gene

Cited by 87 publications

References 4 publications

Androgen insensitivity syndrome: clinical features and molecular defects

Androgen insensitivity syndrome: clinical features and molecular defects

A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation

Kennedy's Disease

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