| First Author | Riepe FG | Year | 2005 |
| Journal | Endocrinology | Volume | 146 |
| Issue | 6 | Pages | 2563-74 |
| PubMed ID | 15731361 | Mgi Jnum | J:109470 |
| Mgi Id | MGI:3628995 | Doi | 10.1210/en.2004-1563 |
| Citation | Riepe FG, et al. (2005) Congenital adrenal hyperplasia: the molecular basis of 21-hydroxylase deficiency in H-2(aw18) mice. Endocrinology 146(6):2563-74 |
| abstractText | 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. |
