Cyp11b1 null mouse, a model of congenital adrenal hyperplasia.
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.
Mullins
Linda J
LJ
Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom.
Peter
Audrey
A
Wrobel
Nicola
N
McNeilly
Judith R
JR
McNeilly
Alan S
AS
Al-Dujaili
Emad A S
EA
Brownstein
David G
DG
Mullins
John J
JJ
Kenyon
Christopher J
CJ
D000311:Adrenal Glands / Q000201:enzymology* / Q000473:pathology; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D003338:Corpus Luteum / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D005091:Exons; D005260:Female; D005938:Glucocorticoids / Q000172:deficiency; D018149:Glucose Intolerance / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000201:enzymology* / Q000473:pathology; D007247:Infertility, Female / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008901:Mineralocorticoids / Q000097:blood; D010913:Pituitary-Adrenal System / Q000201:enzymology* / Q000473:pathology; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics
D005938:Glucocorticoids; D008901:Mineralocorticoids; D013252:Steroid 11-beta-Hydroxylase