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Congenital Adrenal Hyperplasia: The Molecular Basis of 21-Hydroxylase Deficiency in H-2^aw18 Mice

Division of Paediatric Endocrinology (F.G.R., W.G.S., N.K.), Department of Paediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Christian-Albrechts-Universität Kiel, 24105 Kiel, Germany; and Institute of Technical Biochemistry (S.T., J.P.), University of Stuttgart, 70569 Stuttgart, Germany

Address all correspondence and requests for reprints to: Prof. Dr. med. Wolfgang G. Sippell, Division of Paediatric Endocrinology, Department of Paediatrics, Christian-Albrechts-University of Kiel, Schwanenweg 20, D-24105 Kiel, Germany. E-mail: sippell{at}pediatrics.uni-kiel.de.

The mouse strain H-2^aw18 shows typical characteristics of 21-hydroxylase deficiency (21-OHD). A deletion of the active Cyp21a1 gene has been postulated; however, the changes on the nucleotide level are still unknown. To investigate whether this animal model, the only one available, is suitable for studying congenital adrenal hyperplasia in man, a detailed analysis of the Cyp21 locus has been performed to ascertain the genetic cause of 21-OHD in H-2^aw18 mice. We demonstrate that 21-OHD is caused by unequal crossing over between the active Cyp21a1 gene and the pseudogene resulting in a hybrid Cyp21a1-Cyp21a2-p gene including a partial deletion of Cyp21a1. Next to several pseudogene-specific point mutations, various novel missense mutations and a nonsense mutation are present. Enzyme activity for each point mutation has been determined in vitro and the structure-function relationship has been studied by sequence conservation analysis and a three-dimensional murine 21-hydroxylase protein (Cyp21) structure model. The mutations are classified in three classes: I, no or minor decrease in enzyme activity: R238Q, P465L, R361K, A362V, P458L; II, loss of enzyme activity caused by inefficient electron flux: R346H, R400C; III, loss of activity due to deficient substrate binding: I462F, L464F. The combination of in vitro protein expression and three-dimensional structure modeling provides a valuable tool to understand the role of the different mutations and polymorphisms on the resulting enzyme activity. The underlying genetic mechanisms are also known to be responsible for 21-OHD in humans, so rodent 21-OHD turns out to be an excellent genetic model for studying the human disease.

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