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Schoeller Junkmann Prize 2005

Dr. Nils Krone and Dr. Felix G. Riepe

Congenital adrenal hyperplasia: the molecular basis of 21-hydroxylase deficiency in H-2aw18 mice

Pediatric Endocrinology, Pediatric Clinic of the University of Kiel

The mouse strain H-2aw18 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. In order to investigate whether this only available animal model 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-2aw18 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 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 modelling 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.

2005

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