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)

Steroid 11 beta-hydroxylase is encoded by two homologous genes, CYP11B1 and CYP11B2, located on chromosome 8q21-22. CYP11B1 encodes a specific cytochrome P-450 (P-450c11) necessary for cortisol biosynthesis, with predominantly 11 beta-hydroxylase and moderate 18-hydroxylase activity, whereas CYP11B2 encodes another isozyme (P-450cmo) necessary for aldosterone biosynthesis, with 11 beta-hydroxylase, 18-hydroxylase and 18-oxidase activities (the latter two termed corticosterone methyl-oxidase I and II; CMO-I and II, respectively). Two steroid biosynthetic defects, both relatively frequent in Israel, are caused by specific mutations in each of these genes. 11 beta-Hydroxylase deficiency is frequent among Jews from Morocco (1 in 5000 to 7000 births), and is characterized by virilization, hypertension, impaired cortisol biosynthesis, and increased deoxycorticosterone and androgens. Affected individuals have a single base substitution in exon 8 of CYP11B1, codon 448, from CGC (arginine) to CAC (histidine). This sequence, normally absent in CYP11B2, constitutes a true point mutation within the heme binding domain of CYP11B1 that results in marked impairment of enzymatic activity. The clinical expression is characterized by a wide range of variability in the signs of both androgen and mineralocorticoid excess, even though an identical mutation was found in all but one of the affected alleles examined. CMO-II deficiency is frequent among Jews from Iran (1 in 4000 births), and is characterized by a typical salt-wasting syndrome, increased 18-hydroxycorticosterone, impaired aldosterone biosynthesis, and a high ratio of these steroids. No mutation was found in CYP11B1, but all individuals affected were homozygous for two missense mutations in CYP11B2. The first, in exon 3, codon 181, from CGG (arginine) to TGG (tryptophane) is a mutation that completely abolishes both CMO-I and II activities, whereas the second, in exon 7, codon 386, from GTG (valine) to GCG (alanine) is a more conservative substitution that produces only a minimal reduction in CMO-I activity. Individuals homozygous for either one of these mutations are asymptomatic.
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PMID:Mutations in human 11 beta-hydroxylase genes: 11 beta-hydroxylase deficiency in Jews of Morocco and corticosterone methyl-oxidase II deficiency in Jews of Iran. 848 57

Recently, we demonstrated a previously unknown high rate of de novo mutations of the androgen receptor (AR) gene in androgen insensitivity syndrome (AIS) with some resulting in somatic mosaicism of mutant and wild type AR alleles. However, data on the genotype-phenotype relationship in the latter patients are sparse. We present here a 46,XY newborn with ambiguous genitalia carrying a mosaic of an 866 GTG (Val) --> ATG (Met) mutation with the wild type AR gene. This mutation has usually been associated with complete AIS. Accordingly, we found markedly impaired transactivation due to the mutant Met866 AR. Essential information arose from Scatchard analysis of methyltrienolone binding on cultured genital skin fibroblasts. We demonstrated for the first time the expression of two functionally different ARs (Kd1: 5.58 nM = mutant, Kd2: 0.06 nM = wild type) in one AIS individual. This finding not only represents an important confirmation for the presence of the somatic mosaicism in the patient, it also indicates the most likely molecular mechanism responsible for the unexpectedly strong virilization of the patient: Androgen action through the wild type AR expressed by part of the somatic cells. The present case clearly demonstrates the molecular mechanism by which somatic mosaicism of the androgen receptor gene can modulate in vivo androgen action. It underlines the importance of particular notice on somatic mosaicism in all androgen insensitivity syndrome patients carrying de novo mutations of the androgen receptor gene.
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PMID:Expression of two functionally different androgen receptors in a patient with androgen insensitivity. 1048 99

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