Cyp11b1 Null Mouse, a Model of Congenital Adrenal Hyperplasia

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2008; 284(6):3925-34. DOI: 10.1074/jbc.M805081200
Source: PubMed

ABSTRACT Patients with congenital adrenal hyperplasia arising from mutations of 11beta-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 11beta-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 11beta-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.

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    • "Thus , all of the mechanisms likely modulating cAMP levels also likely modulate p44 / p42 mapk activation and function . This is per - haps why the absence of mutations in MC2R ( review in Clark and Weber , 1998 ) or the absence of the key markers of zona glomeru - losa ( Lee et al . , 2005 ) or zona fasciculata ( Mullins et al . , 2009 ) affect not only steroidogenesis , but also the structural organization of the gland ."
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