Mutations of androgen receptor gene in Brazilian patients with male pseudohermaphroditism

Cabral, Daniela Farias; Maciel‐Guerra, Andréa T.; Hackel, Christine

doi:10.1590/s0100-879x1998000600008

Cited by 8 publications

(6 citation statements)

References 15 publications

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“…A smaller amino acid residue at this position (mutation to glutamine in hAR) should have a dramatic impact on ligand binding as the stabilization of the A-ring would be severely hampered due to the lack of an electrostatic interaction (47,48). A similar effect has been reported for the hPR receptor where a mutation (R766H) resulted in a low or even non-detectable binding affinity.…”

mentioning

confidence: 77%

Structural Evidence for Ligand Specificity in the Binding Domain of the Human Androgen Receptor

Matías¹,

Donner²,

Coelho³

et al. 2000

Journal of Biological Chemistry

542

265

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The crystal structures of the human androgen receptor (hAR) and human progesterone receptor ligandbinding domains in complex with the same ligand metribolone (R1881) have been determined. Both threedimensional structures show the typical nuclear receptor fold. The change of two residues in the ligandbinding pocket between the human progesterone receptor and hAR is most likely the source for the specificity of R1881 to the hAR. The structural implications of the 14 known mutations in the ligand-binding pocket of the hAR ligand-binding domains associated with either prostate cancer or the partial or complete androgen receptor insensitivity syndrome were analyzed. The effects of most of these mutants could be explained on the basis of the crystal structure. Androgen (AR)1 and progesterone receptors (PR) are members of the superfamily of nuclear receptors that includes the steroid receptors, among others, as well as the vitamin D, thyroid, retinoic acid receptors, and the so-called orphan receptors. In addition, AR and PR are members of a group of four closely related steroid receptors including the mineralocorticoid receptor and the glucocorticoid receptor recognizing the same hormone response element. In general, steroid receptors are comprised of five to six domains and act as ligand-activated transcription factors that control the expression of specific genes. To date, no experimentally determined three-dimensional structure is available for a complete receptor. During the past few years, x-ray structures have been published for two of the domains, the DNA-binding domain as well as for a number of ligand-binding domains (LBD) including LBD⅐ligand complexes of the estrogen receptor ␣ and ␤, the PR, the vitamin D receptor, the retinoic acid receptors (X,RXR; acid, RAR), the thyroid hormone receptor, and the peroxisome proliferatoractivated receptors (1-13). Despite the low sequence homology of as low as 20% between the LBDs of different nuclear receptor families, all these proteins share a similar fold. They are comprised of up to 12 helices and a small ␤-sheet arranged in a so-called ␣-helical sandwich, a kind of fold that up to now has only been observed for the LBDs of nuclear receptors. Depending on the nature of the bound ligand, agonist, or antagonist, the carboxyl-terminal helix H12 is found in either one of two orientations. In the agonist-bound conformation, helix H12 serves as a "lid" to close the ligand-binding pocket (LBP), whereas in the antagonist-bound conformation helix H12 is positioned in a different orientation thus opening the entrance to the LBP.Androgens and their receptors play an important role in male physiology and pathology.

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mentioning

confidence: 77%

Structural Evidence for Ligand Specificity in the Binding Domain of the Human Androgen Receptor

Matías¹,

Donner²,

Coelho³

et al. 2000

Journal of Biological Chemistry

542

265

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“…aceitadores que afetam o processamento do RNA (CABRAL et al, 1998). Mais de 300 mutações no gene do AR responsáveis pela AIS já foram descritas (CORRÊA et al, 2005).…”

Section: Discussionunclassified

Síndrome da Insensibilidade Androgênica: perfil clínico e epidemiológico de uma série de casos

Mota

Leão

Oliveira

et al. 2012

cmbio

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Introdução: Os Distúrbios do Desenvolvimento Sexual (DDS) resultam de uma interação anormal de fatores genéticos e hormonais implicados no desenvolvimento embrionário da determinação e diferenciação sexual. Os indivíduos com cariótipo 46, XY que apresentaram virilização deficiente da genitália externa são classificados como tendo um quadro sindrômico de Distúrbio do Desenvolvimento Sexual (46, XY DDS), incluindo entre esses a Síndrome da Insensibilidade Androgênica (AIS). Vários genes já foram reconhecidos por sua participação na formação das gônadas e genitálias (interna e externa) entre eles o gene do Receptor de Andrógenos (AR). Objetivo: Analisar os aspectos sócio-epidemiológicos e clínicos de indivíduos com diagnóstico sindrômico de 46, XY Distúrbio do Desenvolvimento Sexual (46,XY DDS) matriculados no Ambulatório de Genética (C-HUPES-UFBA). Metodologia: 13 pacientes com 46, XY DDS e suspeita diagnóstica de AIS, foram selecionados para se traçar o perfil clínico e epidemiológico. Resultados: Entre os pacientes estudados, 07 foram diagnosticados como PAIS e 06 como CAIS, tendo como o sexo de criação, respectivamente, o masculino e o feminino; a média de idade na primeira consulta foi de 06 anos. Cerca de 38% apresentavam história familiar positiva. O motivo de encaminhamento mais frequente foi hipospádia e genitália ambígua. A média do comprimento do falus foi de 2,77 cm. A localização mais comum das gônadas foi na bolsa escrotal. Apenas dois pacientes apresentaram mais de um orifício perineal. Dois pacientes fizeram tratamento medicamentoso e dez foram submetidos à cirurgia corretiva da genitália. Conclusão: Na população estudada o diagnóstico foi mais tardio, isso requer ações sócio-educativas nessa região para incentivar o rápido encaminhamento dos pacientes para diagnóstico e tratamento precoce. Abstract Introduction: Disorders of Sexual Development (DSD) result from an abnormal interaction of genetic and hormonal factors involved in determining embryonic development and sexual differentiation. Individuals with 46, XY karyotype who presented deficient virilization of the external genitalia are classified as having a syndrome of Sexual Development Disorder (46, XY DSD), including those between Androgen Insensitivity Syndrome (AIS). Several genes have been recognized for their participation in the formation of gonads and genitalia (internal and external) including the gene Androgen Receptor (AR). Objective: The aim of this study is to analyze the socio-epidemiological and clinical syndromic diagnosis of individuals with 46, XY disorders of sexual development (46, XY DSD) enrolled in the Genetics Clinic (C-HUPES-UFBA). Methods: we selected 13 patients with clinical diagnosis of AIS and traced the clinical and epidemiological profile. Results: Among the patients studied, 07 were diagnosed as CAIS and 06 as PAIS, and with the sex of rearing, respectively, the male and female and the average age at diagnosis was 06 years. About 38% had a positive family history. The most common reason for referral was hypospadias and ambiguous genitalia. The average length of falus was 2.77 cm. The most common location was the gonads in the scrotum. Only two patients had more than one hole perineal. Two patients received drug treatment and ten underwent corrective surgery of the genitalia. Conclusion: In this study population were diagnosed later, this requires social and educational actions in the region to encourage the rapid referral of patients for early diagnosis and treatment.

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“…Dezenove mutações distintas no AR já haviam sido descritas em 31 pacientes brasileiros portadores de AIS, porém não incluíam a P766A (7,(12)(13)(14). Apesar de mutações neste gene serem bastante freqüentes, este é o segundo relato de diagnóstico molecular em gêmeas com AIS e a segunda família descrita com esta mutação na literatura.…”

Section: Discussionunclassified

Insensibilidade completa aos andrógenos em pacientes brasileiras causada pela mutação P766A no gene do receptor androgênico

Corrêa

Wey

Billerbeck

et al. 2005

Arq Bras Endocrinol Metab

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RESUMOA síndrome de insensibilidade aos andrógenos é uma doença rara ligada ao X, causada por mutações no gene do receptor androgênico (AR), associada a uma variedade de fenótipos em indivíduos 46,XY. Avaliamos duas irmãs gêmeas de 23 anos com sexo social feminino encaminhadas por amenorréia primária, e que apresentavam gônadas palpáveis na região inguinal e cariótipo 46,XY. A ultra-sonografia pélvica não evidenciou útero. As dosagens basais revelaram concentrações elevadas de LH (35 e 42U/L), normais de FSH (7,9 e 7,8U/L) e altas de testosterona (1330 e 1660ng/dl). O estudo molecular identificou uma rara mutação missense no exon 5 do gene do AR com a troca de uma prolina por uma alanina na posição 766 da proteína. O aminoácido prolina 766 do AR é altamente conservado entre as espécies e situa-se em região correspondente ao domínio de ligação ao andrógeno. Androgen insensitivity syndrome (AIS) is a rare X-linked disorder, caused by mutations in the androgen receptor gene (AR), associated with a variety of phenotypes in 46,XY individuals. We studied two 23 year-old twinsisters with female social sex referred due to primary amenorrhea, who exhibited bilateral palpable gonads in the inguinal region and a 46,XY karyotype. The uterus was absent in pelvic sonograms. Basal LH levels were elevated (35 and 42U/L), with normal FSH (7.9 and 7.8U/L) and high testosterone levels (1330 and 1660ng/dl). The molecular analysis identified a missense mutation in exon 5 of AR gene that changed a proline to an alanine at position 766 of the protein. Proline 766 is a highly conserved amino acid in the AR of several species and is located in the androgen binding domain. O S ANDRÓGENOS SÃO IMPORTANTES HORMÔNIOS esteróides com funções específicas na expressão do fenótipo masculino. Estes hormônios têm participação fundamental no processo de diferenciação sexual masculina, além do seu papel no desenvolvimento e manutenção dos caracteres sexuais secundários, e durante a iniciação e manutenção da espermatogênese. Os principais andrógenos circulantes em mamíferos são a testosterona e seu

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Mutations of androgen receptor gene in Brazilian patients with male pseudohermaphroditism

Cited by 8 publications

References 15 publications

Structural Evidence for Ligand Specificity in the Binding Domain of the Human Androgen Receptor

Structural Evidence for Ligand Specificity in the Binding Domain of the Human Androgen Receptor

Síndrome da Insensibilidade Androgênica: perfil clínico e epidemiológico de uma série de casos

Insensibilidade completa aos andrógenos em pacientes brasileiras causada pela mutação P766A no gene do receptor androgênico

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