ECE2023 Oral Communications Oral Communications 5: Adrenal and Cardiovascular Endocrinology 1 (6 abstracts)
CYP21A2-R484Q mice, a humanized mutant animal model for congenital adrenal hyperplasia
Shamini Ramkumar Thirumalasetty 1 , Tina Schubert 1 , Ronald Naumann 2 , Ilka Reichardt 3 , Marie Luise Rohm 1 , Dana Landgraf 1 , Florian Gembardt 4 , Mirko Peitzsch 5 , Michaela F Hartmann 6 , Mihail Sarov 3 , Stefan A Wudy 6 , Nicole Reisch 7 , Angela Huebner 1 & Katrin Koehler 1
1Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Division of Paediatric Endocrinology and Diabetes, Dresden, Germany; 2Max Planck Institute of Molecular Cell Biology and Genetics, Transgenic Core Facility, Dresden, Germany; 3Max Planck Institute of Molecular Cell Biology and Genetics, Genome Engineering Facility, Dresden, Germany; 4Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Division of Nephrology, Medizinische Klinik III, Dresden, Germany; 5Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Institute of Clinical Chemistry and Laboratory Medicine, Dresden, Germany; 6Justus Liebig Universität, Paediatric Endocrinology and Diabetology, Center of Child and Adolescent Medicine, Giessen, Germany; 7Ludwig-Maximilians-Universität München, Medizinische Klinik und Poliklinik IV, Munich, Germany
Congenital Adrenal hyperplasia (CAH) refers to a group of autosomal-recessive inherited disorders of impaired adrenal steroidogenesis. The most common form is 21-hydroxylase deficiency (21-OHD) caused by mutations in the CYP21A2 gene. Patients lack glucocorticoids and in some cases mineralocorticoids, and present with androgen excess causing hypoglycemia, live-threatening salt wasting, virilisation, and precocious puberty. Treatment includes the replacement of deficient steroid hormones and restoring negative feedback towards CRH and pituitary ACTH secretion to suppress hyperandrogenemia. This often requires the administration of supra-physiological doses of glucocorticoids which may cause significant treatment-related side effects. As recent advances have shed light on the steroidogenic mechanisms and the genetics of CAH, multiple novel treatment approaches are being developed to holistically manage CAH patients, to minimize glucocorticoid exposure and to achieve better patient outcomes. However, novel drugs lack effective in-vivo models for pre-clinical testing. In this work, we present the first viable and humanized mouse model in which the mouse gene Cyp21a1 is replaced by the human orthologue CYP21A2 with the integrated human point mutation p.R484Q. Twenty-weeks-old homozygous mice showed hyperplastic adrenals and an expression of the human CYP21A2 gene. Tandem mass spectrometry measurements of plasma at 20 weeks showed decreased corticosterone and 11-deoxycorticosterone levels in both male and female homozygous animals. Additionally, progesterone levels in homozygous mice were significantly higher (P<0.01) than in wildtype mice. We also observed increased aldosterone levels in female mutants, whereas blood pressure did not differ between wildtype and mutant mice strains. ACTH levels were elevated in both male and female homozygous animals. 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 were fertile with normal appearing testes, females were infertile, remaining in the diestrus phase with a reduced number of ovarian follicles. In conclusion, we show that the humanized mutant CYP21A2 mice may represent an excellent animal CAH model to test novel treatment strategies. It will potentially contribute to achieving overarching treatment goals to prevent comorbidities resulting from hormone – related derangements and treatment-related side effects among CAH patients. The animal model will play a pivotal role in supporting the transition from basic research to clinical application.
Keywords: Adrenals, CAH, animal models
Volume 90
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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