title: Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation.
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-Arg(426)His, which has not yet been described to represent a common pseudogene sequence. In vitro expression experiments showed the Arg(426)His 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.
authors.affiliation: Department of Internal Medicine III, Division of Endocrinology and Metabolism, University of Vienna, Waeringer Guertel 18-20, A-1090 Vienna, Austria. sabina.baumgartner-parzer@akh-wien.ac.at
authors.forename: S M
authors.initials: SM
authors.lastname: Baumgartner-Parzer
authors.forename: E
authors.initials: E
authors.lastname: Schulze
authors.forename: W
authors.initials: W
authors.lastname: Waldhäusl
authors.forename: S
authors.initials: S
authors.lastname: Pauschenwein
authors.forename: S
authors.initials: S
authors.lastname: Rondot
authors.forename: P
authors.initials: P
authors.lastname: Nowotny
authors.forename: K
authors.initials: K
authors.lastname: Meyer
authors.forename: H
authors.initials: H
authors.lastname: Frisch
authors.forename: F
authors.initials: F
authors.lastname: Waldhauser
authors.forename: H
authors.initials: H
authors.lastname: Vierhapper
mesh_terms: D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics*; D000483:Alleles; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D013255:Steroid 21-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D013255:Steroid 21-Hydroxylase