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Endocrine Abstracts (2015) 38 P388 | DOI: 10.1530/endoabs.38.P388

SFEBES2015 Poster Presentations Steroids (49 abstracts)

A novel animal model to explore the whole-organism response to 21-hydroxylase deficiency

Andreas Zaucker , Tulay Guran , Nazia Thakur , Angela Taylor , Aliesha Griffin & Nils Krone


University of Birmingham, Birmingham, West Midlands, UK.


Congenital adrenal hyperplasia (CAH) is one of the most common inherited disorders. The majority of CAH cases are due to 21-hydroxylase deficiency (21-OHD) caused by mutations in CYP21A2. Because of the profound impact of steroids on physiology and gene expression, the imbalances in steroid hormones resulting from 21-OHD are supposedly leading to a whole-organism response on transcriptome and metabolome level. The systemic consequences of severe 21-OHD during early development and adult life remain poorly understood. This gap in knowledge is due to a lack of suitable animal models, as Cyp21a2 knock-out mice are not viable. Therefore, we have developed a zebrafish model for 21-OHD. A single 21-hydroxylase gene is annotated in the zebrafish genome based on sequence homology, cyp21a2 (ENSDARG00000037550). Our in silico analysis of the Cyp21a2 protein sequence suggests a sufficient degree of similarity for the usage of zebrafish cyp21a2 to model human 21-OHD in vivo: The majority of residues corresponding to CAH causing mutations are conserved and the predicted impact on protein structure caused by known CAH mutations is similar. In contrast to control transfected cells, zebrafish Cyp21a2 expressing COS7 cells convert 17-hydroxyprogesterone into 11-deoxycortisol (measured by LC/MSMS) at a similar rate as human CYP21A2, confirming the correct annotation of cyp21a2 as zebrafish 21-OH. In addition, we determined the spatio-temporal expression patterns of cyp21a2 by RNA- in situ hybridisation and RT-PCR throughout early development (first five days) and in adult tissues. Early cyp21a2 expression is restricted to the interrenal gland (zebrafish adrenal counterpart) and the brain, where it is also expressed in adults. To further explore the in vivo consequences of Cyp21a2 deficiency we created several cyp21a2 null-allele zebrafish lines employing a TALEN (transcription activator-like effector nuclease) genomic engineering strategy. This new in vivo model will provide novel insights into the whole organism response and pathophysiology of 21-hydroxylase deficiency.

Volume 38

Society for Endocrinology BES 2015

Edinburgh, UK
02 Nov 2015 - 04 Nov 2015

Society for Endocrinology 

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