Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome

Chávez, Bertha; Méndez, Juan Pablo; Ulloa‐Aguirre, Alfredo; Larrea, Fernando; Vilchis, Felipe

doi:10.1007/s100380170021

Cited by 29 publications

(18 citation statements)

References 37 publications

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“…This notion was buttressed by clinical evidence. Failure of such matching, as shown by the naturally occurring mutation Q711E in the androgen receptor, would cause androgen insensitivity syndrome (AIS) (31). The different response of the Glu 282 carboxylate group to the corresponding hydroxyl or keto group of steroids, illustrated by our crystal structures, strongly supports the above concept.…”

Section: Discussionsupporting

confidence: 57%

Cofactor Hydrogen Bonding onto the Protein Main Chain Is Conserved in the Short Chain Dehydrogenase/Reductase Family and Contributes to Nicotinamide Orientation

Shi

Lin

2004

Journal of Biological Chemistry

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Human estrogenic 17␤-hydroxysteroid dehydrogenase (17␤-HSD1), a member of the short chain dehydrogenase/reductase (SDR) family, is responsible for the biosynthesis of all active estrogens. The crystal structures of two C19-steroid ternary complexes (17␤-HSD1-androstanedione-NADP and 17␤-HSD1-androstenedione-NADP) reveal the critical role of Leu 149 in regulating the substrate specificity and provide novel insight into the different fates of a conserved glutamate residue in the estrogen-specific proteins upon the binding of the keto and hydroxyl groups of steroids. The whole NADP molecule can be unambiguously defined in the NADP binary complex, whereas both ternary complexes show that the nicotinamide moiety of NADP cannot be located in the density maps. In both ternary complexes, the expected position of carboxamide oxygen of NADP is occupied by a water molecule, which makes a bifurcated hydrogen bond with the O3 of C19-steroid and the main chain nitrogen of Val 188 . These results demonstrate that the hydrogen bonding interaction between the main chain amide group and the carboxamide group of NAD(P)(H) plays an important role in anchoring the nicotinamide ring to the enzyme. This finding is substantiated by structural analyses of all 33 NAD(P)(H) complexes of different SDR proteins, because 29 structures of 33 show this interaction. This common feature reveals a general mechanism among the SDR family, providing a rational basis for inhibitor design against biologically relevant SDR targets.

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Section: Discussionsupporting

confidence: 57%

Cofactor Hydrogen Bonding onto the Protein Main Chain Is Conserved in the Short Chain Dehydrogenase/Reductase Family and Contributes to Nicotinamide Orientation

Shi

Lin

2004

Journal of Biological Chemistry

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“…In addition, point mutations can also cause splice site alterations, which alter mRNA processing [13,20,27,28] . This kind of nucleotide substitution is relatively rare and was not observed in this study.…”

Section: Discussionmentioning

confidence: 99%

Novel and Recurrent Mutations in Patients with Androgen Insensitivity Syndromes

et al. 2005

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Background/Aims: Androgen insensitivity syndrome (AIS) caused by mutations within the androgen receptor gene represents a variety of phenotypes from females with 46,XY karyotype over individuals with ambiguous genitalia to infertile males. Methods: We studied 24 patients with AIS by sequencing androgen receptor gene. 19 of the investigated patients were affected by complete androgen insensitivity syndrome (CAIS) and 5 suffered from partial androgen insensitivity syndrome (PAIS). Results: So far we have detected 12 unreported mutations as well as 9 recurrent mutations (3 recurrent mutations were detected twice) in exons 2–8 of the androgen receptor gene. Three of the novel mutations cause a frameshift with subsequent premature termination and were found in patients with CAIS. These frameshifts were induced by single nucleotide deletion or insertion, or in one case by a 13-bp deletion, respectively. Another premature stop codon found in a CAIS patient results from an already reported nucleotide substitution in exon 5. Furthermore, in a CAIS patient we found a novel duplication of codon 788. All other mutations caused single base substitutions spread through exons 2–8 and were associated with CAIS or PAIS. Conclusions: We report a broad spectrum of different mutations within the AR gene leading to various manifestations of AIS. Apart from truncating mutations, a reliable genotype/phenotype correlation cannot be established. Therefore, modifying factors must be effective.

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“…Another mutation close to the position of F826, F827V, found in an individual classified as having CAIS, was reported to result in just 20 % less ligand binding affinity in genital skin fibroblasts (Chavez et al, 2001a). The AR mutant L830V was also found in a CAIS individual (Chavez et al, 2001b).…”

Section: Tif2 Co-activation Of Ar Mutants F826lmentioning

confidence: 99%

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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Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome

Cited by 29 publications

References 37 publications

Cofactor Hydrogen Bonding onto the Protein Main Chain Is Conserved in the Short Chain Dehydrogenase/Reductase Family and Contributes to Nicotinamide Orientation

Cofactor Hydrogen Bonding onto the Protein Main Chain Is Conserved in the Short Chain Dehydrogenase/Reductase Family and Contributes to Nicotinamide Orientation

Novel and Recurrent Mutations in Patients with Androgen Insensitivity Syndromes

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

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