Defects in the HSD11 gene encoding 11?-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency

Nikkila, Heli; Tannin, Grace M.; New, Maria I.; Taylor, Norman; Kalaitzoglou, George; Monder, Carl; White, Perrin C.

doi:10.1007/bf00866357

Cited by 8 publications

(11 citation statements)

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“…Until recently, the gene 11b-HSD type 1 has been studied only by Nikkila and colleagues (18) in relation to hypertension and by Jamieson and colleagues in a woman with oligomenhorrea, hirsutism and acne (19). Both studies failed to identify any mutation or polymorphism of this gene associated with the pathology considered.…”

Section: Discussionmentioning

confidence: 96%

“…The primer sequences for PCR of human 11b-HSD1 gene were mainly based on a previous description (18); however, we have improved the procedure in order to increase the annealing temperature and obtain a more speci®c ampli®cation, and some entirely new primers were designed due to the recent availability of the complete genomic sequence (see Bioinformatics analysis below). All primer sequences are shown in Table II.…”

Section: Polymerase Chain Reaction (Pcr)mentioning

confidence: 99%

“…The gene encoding this enzyme is approximately 9 kb in length and has been localized on chromosome 1 (11). To date, no structural alterations of this gene has been reported, although a mutational screening was performed in patients with AME (18) and in a woman with oligomenhorrea, hirsutism and acne (19). Recent studies have investigated 11b-HSD1 isozyme function in the adipose tissues.…”

Section: Introductionmentioning

confidence: 96%

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LACK OF MUTATIONS OF TYPE 1 11β-Hydroxysteroid DEHYDROGENASE GENE IN PATIENTS WITH ABDOMINAL OBESITY

Caramelli

Strippoli²,

Giacomi³

et al. 2001

Endocrine Research

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There is increasing evidence that in human obesity, particularly the abdominal phenotype, the activity of the hypothalamic-pituitary-adrenal (HPA) axis is disregulated. At least two distinct alterations have been reported: one is characterized by several neuroendocrine abnormalities and hyperresponsiveness of the HPA axis to different neuropeptides, the other is characterized by elevated cortisol traffic and probably by supranormal cortisol production. The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) enzymes interconvert cortisol and cortisone in human. Two different isoforms have been identified. A possible modification of the activity of the enzyme 11beta-HSD1 in subjects with abdominal obesity has been described in the literature. We decided to test the hypothesis that mutated isoforms of type 11beta-HSD1 protein could be responsible for alterations of cortisol metabolism in patients with abdominal obesity. A mutational screening of the whole coding sequence and exon-flanking regions of the 11B-HSD1 gene has been performed in 8 patients. The main results of our study are the exclusion of a common association of 11beta-HSD1 mutations to obesity and the identification of two novel allelic variants for the gene 11beta-HSD1 in the Italian population, not previously described in any database.

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Section: Discussionmentioning

confidence: 96%

Section: Polymerase Chain Reaction (Pcr)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

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LACK OF MUTATIONS OF TYPE 1 11β-Hydroxysteroid DEHYDROGENASE GENE IN PATIENTS WITH ABDOMINAL OBESITY

Caramelli

Strippoli²,

Giacomi³

et al. 2001

Endocrine Research

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“…However, there have been no published reports thus far of mutations in coding sequences or intron-exon junctions of HSD11B1 in ACRD patients [27,29]. Instead, two polymorphisms in intron 3 of HSD11B1 were detected and found to be in complete linkage disequilibrium: 83 557insA (actually 1931 bp downstream of the initial A in the coding sequence) and 83 597T>G (1971 bp from the Roles of 11-HSD1 and H6PD White et al 455 Figure 1 Schematic of factors influencing activity of 11b-hydroxysteroid dehydrogenase type 1 in the endoplasmic reticulum A simplified cell is shown.…”

Section: Genetics Of Apparent Cortisone Reductase Deficiencymentioning

confidence: 99%

Physiological roles of 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase

White

Rogoff

McMillan

2008

Current Opinion in Pediatrics

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“…In addition, no 11-HSD1 sequence abnormalities were detected on analysis of five patients (2) with the syndrome of Apparent Mineralocorticoid Excess (AME), long suspected to reflect congenitally lowered 11-HSD activity, allowing glucocorticoids to access and activate epithelial mineralocorticoid receptors. The first of these (1) is now termed 11\g=b\-hydroxysteroiddehydrogenase type 1 (11-HSD1), and catalyses the interconversion of cortisol and corticosterone to/from their receptor-inactive 11-keto analogues cortisone and 11dehydrocorticosterone, with NADP/NADPH as preferred co-substrate.…”

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confidence: 99%

11β-Hydroxysteroid dehydrogenase: new answers, new questions

Funder

1996

European Journal of Endocrinology

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There are currently two, distantly related members of the short-chain alcohol dehydrogenase family with 11\g=b\-hydroxysteroiddehydrogenase activity that have been cloned, expressed and characterized. The first of these (1) is now termed 11\g=b\-hydroxysteroiddehydrogenase type 1 (11-HSD1), and catalyses the interconversion of cortisol and corticosterone to/from their receptor-inactive 11-keto analogues cortisone and 11dehydrocorticosterone, with NADP/NADPH as preferred co-substrate. 11\g=b\-Hydroxysteroiddehydrogenase type 1 is found at high abundance in liver, testis, lung and renal proximal tubule; its Km for cortisone and 11-dehydrocorticosterone is an order of magnitude lower than for cortisol and corticosterone, but is commonly in the micromolar range. The combination of low affinity, predominant reductase activity and tissue distribution makes 11-HSD1 an unlikely candidate protector of epithelial mineralocorticoid receptors, which have similar high affinity for aldosterone, cortisol and corticosterone. In addition, no 11-HSD1 sequence abnormalities were detected on analysis of five patients (2) with the syndrome of Apparent Mineralocorticoid Excess (AME), long suspected to reflect congenitally lowered 11-HSD activity, allowing glucocorticoids to access and activate epithelial mineralocorticoid receptors.The second human isoform has been cloned and expressed more recently (3), and has much higher (35% vs 15%) amino acid identify with 17-HSD2 than 11-HSD1. Human 11-HSD2 has a much lower Km for physiological glucocorticoids than 11-HSD1 (cortico¬ sterone,~5 nmol/1; cortisol,~50nmol/1), is NAD dependent and apparently unidirectional. As noted in the study of Diederich et al. (4), the subsequent cloning of 11-HSD2 in laboratory animals has allowed its localization to be documented extensively. In all species studied, high levels of 11-HSD2 expression are seen in classical aldosterone target tissues (kidney, colon, parotid); moderate/high levels are also seen in adrenal, pancreas and placenta in some but not all species, which is evidence of possible roles for 11-HSD2 over and above that of excluding physiological glucocorticoids from epithelial mineralocorticoid receptors. That this latter role is, however, crucial has been shown by very recent studies in which mutations in the gene coding for 11-HSD2 have been reported for patients with AME (5-7). More than a dozen kindred have been analysed, and have shown a wide variety of point mutations/deletions that lower or abolish enzyme activity, allowing circulating glucocorticoids access to epithelial mineralocorticoid receptors and thus controlled salt retention. To date, all affected (homozygous) patients have different mutations/ deletions, with the exception of a Zoroastrian Melbourne family of Iranian extraction and two Parsee families from Bombay. Secondly, all affected patients documented to date have the same mutation in both DNA strands, even where consanguinity/endogamy do not appear to be in evidence. Given that 11-HSD2 is thus clearly required for normal...

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Defects in the HSD11 gene encoding 11?-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency

Cited by 8 publications

References 0 publications

LACK OF MUTATIONS OF TYPE 1 11β-Hydroxysteroid DEHYDROGENASE GENE IN PATIENTS WITH ABDOMINAL OBESITY

LACK OF MUTATIONS OF TYPE 1 11β-Hydroxysteroid DEHYDROGENASE GENE IN PATIENTS WITH ABDOMINAL OBESITY

Physiological roles of 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase

11β-Hydroxysteroid dehydrogenase: new answers, new questions

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