Steroid 21-Hydroxylase Deficiency in Mice*

Gotoh, Hiroki; Sagai, Tomoko; Hata, Junichi; Shiroishi, Toshihiko; Moriwaki, Kazuo

doi:10.1210/endo-123-4-1923

Cited by 34 publications

(17 citation statements)

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“…Some corticosterone is released as an intermediate on the way to the final product, aldosterone (23). The most severe symptoms of CAH are caused by 21-hydroxylase, which compromises both aldosterone and cortisol/corticosterone synthesis and markedly affects viability of both humans and mice (24,25).…”

Section: Discussionmentioning

confidence: 99%

Cyp11b1 Null Mouse, a Model of Congenital Adrenal Hyperplasia

Mullins

Peter

Wrobel

et al. 2009

Journal of Biological Chemistry

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Patients with congenital adrenal hyperplasia arising from mutations of 11␤-hydroxylase, the final enzyme in the glucocorticoid biosynthetic pathway, exhibit glucocorticoid deficiency, adrenal hyperplasia driven by unsuppressed hypothalamo-pituitary-adrenal activity, and excess mineralocorticoid activity caused by the accumulation of deoxycorticosterone. A mouse model, in which exons 3-7 of Cyp11b1 (the gene encoding 11␤-hydroxylase) were replaced with cDNA encoding enhanced cyan fluorescent protein, was generated to investigate the underlying disease mechanisms. Enhanced cyan fluorescent protein was expressed appropriately in the zona fasciculata of the adrenal gland, and targeted knock-out was confirmed by urinary steroid profiles and, immunocytochemically, by the absence of 11␤-hydroxylase. The null mice exhibited glucocorticoid deficiency, mineralocorticoid excess, adrenal hyperplasia, mild hypertension, and hypokalemia. They also displayed glucose intolerance. Because rodents do not synthesize adrenal androgens, changes in reproductive function such as genital virilization of females were not anticipated. However, adult homozygote females were infertile, their ovaries showing an absence of corpora lutea and a central proliferation of disorganized steroidogenic tissue. Null females responded normally to superovulation, suggesting that raised systemic progesterone levels also contribute to infertility problems. The model reveals previously unrecognized phenotypic subtleties of congenital adrenal hyperplasia.The final steps leading to the production of glucocorticoids and mineralocorticoids are undertaken by 11␤-hydroxylase and aldosterone synthase, encoded by two closely linked genes, Cyp11b1 and Cyp11b2, respectively, that share 95% sequence homology. In rodents, the common substrate, deoxycorticosterone, is converted into the mineralocorticoid, aldosterone, in the adrenal zona glomerulosa by aldosterone synthase and into corticosterone, the main glucocorticoid, by 11␤-hydroxylase in the zona fasiculata. Cortisol rather than corticosterone is the main glucocorticoid in humans because Cyp17 is expressed in the zona fasciculata. Unlike rodents, human adrenals produce significant amounts of the androgen dehydroepiandrosterone (DHEA). 2 Patients with congenital adrenal hyperplasia (CAH) have a markedly reduced capacity to produce glucocorticoids. In ϳ90% of cases CAH is caused by deficiency of 21-hydroxylase, the penultimate enzyme in the pathways of both aldosterone and cortisol synthesis (1). In 8% of CAH cases, point mutations in or deletion of Cyp11b1 drastically reduce or completely destroy 11␤-hydroxylase activity (2-4).Adrenal hyperplasia is a consequence of increased ACTH secretion in the absence of normal negative feedback control by glucocorticoids of the hypothalamo-pituitary-adrenal axis. In 21-hydroxylase-deficient patients, ACTH drives the production of progesterone and 17-hydroxyprogesterone and channels earlier 17-hydroxylated intermediates in the glucocorticoid pathway toward the synthesis of adr...

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Section: Discussionmentioning

confidence: 99%

Cyp11b1 Null Mouse, a Model of Congenital Adrenal Hyperplasia

Mullins

Peter

Wrobel

et al. 2009

Journal of Biological Chemistry

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“…Genomic DNA was extracted from livers or tails using standard procedures as previously described (18). A 950-bp complementary DNA (cDNA) fragment encoding exons 3 to 9 of the mouse CYP21 cDNA was prepared by PCR using 500 ng of total adrenal RNA (prepared with TRIzol reagent, Gibco BRL, Gaithersburg, MD) and the GeneAmpRNA PCR kit (Perkin Elmer Corp., Foster City, CA).…”

Section: Determination Of Genotypementioning

confidence: 99%

“…In mice, which lack of 17-␣-hydroxylase in the adrenal, the enzymatic blockade results mainly in accumulation of progesterone. The majority of affected mice die within a week if not treated with gluco-and mineralocorticoids (17)(18)(19). Although, the 21-OH deficient mouse is not strictly comparable with human CAH, it may provide a useful model to study the pathophysiology of the disease.…”

mentioning

confidence: 99%

Prenatal Dexamethasone Treatment Does Not Prevent Alterations of the Hypothalamic Pituitary Adrenal Axis in Steroid 21-Hydroxylase Deficient Mice

Tajima

Bornstein

et al. 1999

Endocrinology

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A major difficulty in the clinical management of congenital adrenal hyperplasia (CAH) is adjustment of glucocorticoid doses to suppress ACTH and androgens without causing iatrogenic hypercortisolism. The possibility that structural alterations of the adrenal or a dysfunction of the hypothalamic pituitary adrenal (HPA) axis caused by glucocorticoid deficiency during fetal life contribute to this problem was studied in 21-hydroxylase deficient mice caused by deletion of the cytochrome P-450 21-hydroxylase gene. Homozygotes showed about 200-fold elevations in plasma progesterone, hyperplastic adrenal cortices lacking zonation, and structural alterations of adrenocortical mitochondria. Histochemical studies showed increases in hypothalamic CRH messenger RNA (mRNA) and immunoreactive (ir) CRH, and pituitary POMC mRNA in homozygous mice. VP mRNA levels in PVN perikarya were normal, but irVP in parvicellular terminals of the median eminence was increased in homozygotes. Prenatal dexamethasone treatment (0.5 to 2 microg/day) prevented the increases in CRH mRNA, whereas dexamethasone only partially decreased POMC mRNA levels, and had no effect on serum progesterone levels. The data suggest that intrauterine glucocorticoid deficiency in CAH causes hyperactivity of the hypothalamic-pituitary-corticotroph axis and insensitivity to glucocorticoid feedback. These studies in 21-hydroxylase deficient mice may provide new insights on the mechanism, clinical manifestations and management of some types of human CAH.

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“…4,5 A naturally occurring strain of mouse with deletion of the CYP21 and complement 4 component genes has impaired 21-OH activity and glucocorticoid production leading to hyperproduction of ACTH with adrenocortical hyperplasia and accumulation of precursor steroids. 6,7 Since the mouse adrenal lacks 17-hydroxylase, unlike the human disease, the accumulated precursor is progesterone and no androgenization occurs in this model. Also, the deletion of the gene for complement component C4 makes the 21-hydroxylase-deficient mouse different from the human disease.…”

Section: Introductionmentioning

confidence: 98%