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Mutational Spectrum of the Steroid 21-Hydroxylase Gene in Austria: Identification of a Novel Missense Mutation

Department of Internal Medicine III, Division of Endocrinology and Metabolism, and Department of Pediatrics (H.F., F.W.), University of Vienna, A-1090 Vienna, Austria; and Institute of Pharmacology, University of Heidelberg (E.S., S.R., K.M.), Heidelberg, Germany

Address all correspondence and requests for reprints to: Sabina M. Baumgartner-Parzer, Ph.D., Department of Internal Medicine III, Division of Endocrinology and Metabolism, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: sabina.baumgartner-parzer{at}akh-wien.ac.at

Abstract

This study attempted an analysis of the mutational spectrum of 21-hydroxylase deficiency in 79 unrelated Austrian patients with classical and nonclassical forms of congenital adrenal hyperplasia and their respective 112 family members. Apparent large gene deletions/conversions were present in 31% of the 158 unrelated congenital adrenal hyperplasia alleles, whereas the most frequent point mutations were intron 2 splice (22.8%), I172N (15.8%), V281L (12%), and P30L (7.6%), in line with the frequencies reported for other countries. In 5 of the 12 congenital adrenal hyperplasia alleles carrying a P30L mutation the aberration is based on a single base substitution, whereas the remaining 7 represent part of a CYP21B conversion (1 allele) or CYP21B/21A hybrid gene (6 alleles), the latter characterized by a junction site before intron 2 as indicated by Southern blot, PCR, and sequence analyses.

Previously described mutations were not present in 1.2% of unrelated congenital adrenal hyperplasia alleles, including one female patient presenting with severe genital virilization. Sequence analysis of the complete functional 21-hydroxylase gene revealed an as yet undescribed mutation in exon 10-Arg⁴²⁶His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg⁴²⁶His mutant to exhibit only low enzyme activity toward the natural substrate 17-hydroxyprogesterone corresponding to the degree of disease manifestation in the patient in whom it was found.

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