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Submitted on April 30, 2004
Accepted on September 21, 2004
Division of Pediatric Endocrinology, Department of Pediatrics, Christian-Albrechts-Universität zu Kiel, Universitätsklinikum Schleswig-Holstein (Campus Kiel), Schwanenweg 20, D-24105 Kiel, Germany; Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098 Kiel, Germany
* To whom correspondence should be addressed.
Wolfgang G. Sippell, E-mail: sippell{at}pediatrics.uni-kiel.de
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders most often caused by deficiency of steroid 21-hydroxylase due to mutations in the CYP21 gene. We studied the functional and structural consequences of two novel missense mutations in the CYP21 gene, detected in two simple virilizing CAH patients. Both the male and female patient were compound heterozygous for the novel I77T and A434V point mutations, respectively. The in vitro expression analysis in COS-7 cells revealed a reduced 21-hydroxylase activity in the I77T mutant of 3 ± 2 (SD) % for the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol and of 5 ± 3% for the conversion of progesterone to 11-deoxycorticosterone. The A434V mutant had a residual enzyme activity of 14 ± 2% for 17OHP and 12 ± 6% for progesterone. Substrate affinity was similar in the mutants as in the CYP21 wild-type protein, whereas reaction velocity was markedly decreased in both mutants. These effects could be readily explained by structural changes induced by the mutations, which were rationalized by a 3-dimensional-model structure of the CYP21 protein. We hypothesize that the I77T mutation markedly decreases the reaction product release and/ or substrate entrance to the enzyme's active site, whereas the A434V mutant reduces both the catalytic capacity and the reaction velocity. Studying the enzyme function in vitro helps to understand the phenotypical expression and disease severity of 21-hydroxylase deficiency, and also provides new insights into cytochrome P450 structure-function relationships.
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