ESPE2023 Free Communications Adrenals and HPA Axis (6 abstracts)
Generation and Characterization of a novel Humanized CYP21A2 Knock-in Mouse Model for Congenital Adrenal Hyperplasia
Angela Huebner 1 , Shamini Ramkumar Thirumalasetty 1 , Tina Schubert 1 , Ronald Naumann 2 , Ilka Reichard 2 , Marie Luise Rohm 1 , Dana Landgraf 1 , Florian Gembardt 3 , Michaela F. Hartmann 4 , Stefan A. Wudy 4 , Mirko Peitzsch 5 , Nicole Reisch 6 & Katrin Koehler 1
1Division of Paediatric Endocrinology and Diabetes, Children's Hospital, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 2Transgenic Core Facility, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany. 3Division of Nephrology, Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 4Paediatric Endocrinology and Diabetology, Center for Child and Adolescent Medicine, Justus Liebig Universität Giessen, Giessen, Germany. 5Institute of Clinical Chemistry and Laboratory Medicine, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 6Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universitäts München, Munich, Germany
21-hydroxylase deficiency (21OHD) is the most common form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the CYP21A2 gene. 21OHD causes a wide array of clinical symptoms that result from gluco- and mineralocorticoid deficiency and adrenal androgen excess. In most cases, supra-physiological glucocorticoid doses are necessary which may cause short stature, obesity, hypertension, cardiovascular and metabolic co-morbidity with reduced quality of life. Hence, current steroid substitution regimens have significant limitations, so novel therapeutic strategies are required. In recent years, new therapeutic approaches have emerged including new non-glucocorticoid substances interfering with the HPA axis to minimize adrenal androgen production and to lower external glucocorticoid substitution to physiological levels. However, valuable in-vivo models for pre-clinical testing of such drugs are lacking. Here we present the first viable and humanized knock-in mouse model in which the mouse gene Cyp21a1 is replaced by the human orthologue CYP21A2 with the integrated frequent-occurring human point mutation p.R484Q. Twenty-weeks-old homozygous mice show marked adrenocortical hyperplasia, enhanced expression of the CYP21A2 gene and a weak increase of Cyp11a1 and Cyp11b2 gene expression. Tandem mass spectrometry measurements in mice plasma at 20 weeks show decreased corticosterone and 11-deoxycorticosterone levels in both male and female homozygous animals. Progesterone levels in homozygous mice are significantly higher (P<0.01) than in wildtype mice. We also observed increased aldosterone levels in female mutants whereas blood pressure does not differ between wildtype and mutant mice strains. Tetrahydrocorticosterone (THB), a major glucocorticoid metabolite could be detected in 24-hours-urine in wildtype mice but not in homozygous mutant animals. While mutant male mice are fertile with normal appearing testes, females are infertile, remain in the diestrus phase and present with a reduced number of ovarian follicles and lack of corpus luteum. In parallel, a second mouse strain bearing the I173N mutation was developed. This mutation is frequent in human patients causing simple virilizing or rarely salt wasting CAH. Homozygous mice require dexamethasone treatment during pregnancy and until weaning but are viable without treatment afterwards. Preliminary results show adrenal hyperplasia and alteration in steroidogenic gene expression and steroid profiles. In conclusion, we demonstrate that the humanized mutant CYP21A2 mice may represent an excellent animal CAH model to test novel treatment strategies for CAH patients. We believe that this model(s) will facilitate the transition from basic research into clinical application.
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