Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inadequate androgen action in genetic and gonadal males causes an intersex phenotype. We have analyzed the androgen receptor (AR) gene in male pseudohermaphrodites with normal specific binding of dihydrotestosterone in their genital skin fibroblasts. In five patients with Reifenstein syndrome we have detected a point mutation in the DNA binding domain. They are from two unrelated families and presented with perineoscrotal hypospadias and undescended testes. After puberty they showed small testes, no palpable prostate, micropenis, azoospermia, and gynecomastia. The mutation was discovered when cDNA fragments from three brothers were sequenced. For rapid detection of the mutation in heterozygous and hemizygous carriers, allele-specific PCRs and restriction-analysis techniques have been developed. Relatives of the patients, a group of normal blood donors, and other patients were screened with these methods. Among 41 intersex patients with incomplete virilization, another two brothers presenting with this mutation were identified. The mutation is a guanine-to-adenine transition at nucleotide 2314, which changes the alanine codon (GCC) immediately after the first cysteine of the second zinc finger motif of the AR into a threonine codon (ACC). The mutation was recreated in an AR expression vector, and wild-type as well as mutant ARs were expressed in COS-7 cells. Cotransfection experiments were made using a mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. The ability of the mutant receptor to stimulate transcription of the reporter gene was reduced by about two-thirds, as compared with the wild-type receptor.
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PMID:Point mutation in the DNA binding domain of the androgen receptor in two families with Reifenstein syndrome. 159 12

We recently found that postzygotic de novo mutations occur at the expected high rate of an X-linked recessive mutation in androgen insensitivity syndrome. The resulting somatic mosaicism can be an important molecular determinant of in vivo androgen action caused by expression of the wild-type androgen receptor (AR). However, the clinical relevance of this previously underestimated genetic condition in androgen insensitivity syndrome has not been investigated in detail as yet. Here, we present the clinical and molecular spectrum of somatic mosaicism considering all five patients with mosaic androgen insensitivity syndrome, whom we have identified since 1993: Patient 1 (predominantly female, clitoromegaly), 172 TTA(Leu)/TGA(Stop); patient 2 (ambiguous), 596 GCC(Ala)/ACC(Thr); patient 3 (ambiguous), 733 CAG(Gln)/ CAT(His); patient 4 (completely female), 774 CGC(Arg)/TGC (Cys); and patient 5 (ambiguous), 866 GTG(Val)/ATG(Met). Serum sex hormone binding globulin response to stanozolol, usually correlating well with in vivo AR function, was inconclusive for assessment of the phenotypes in all tested mosaic individuals. An unexpectedly strong virilization occurred in patients 1, 3, and 5 compared with phenotypes as published with corresponding inherited mutations and compared with the markedly impaired transactivation caused by the mutant ARs in cotransfection experiments. Only the prepubertal virilization of patients 2 and 4 matched appropriately with transactivation studies (patient 4) or the literature (patients 2 and 4). However, partial pubertal virilization in patient 4 caused by increasing serum androgens and subsequent activation of the wild-type AR could not be excluded. We conclude that somatic mosaicism is of particular clinical relevance in androgen insensitivity syndrome. The possibility of functionally relevant expression of the wild-type AR needs to be considered in all mosaic individuals, and treatment should be adjusted accordingly.
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PMID:Clinical and molecular spectrum of somatic mosaicism in androgen insensitivity syndrome. 1059 24