Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia

V. Dolžan, J. Sólyom, G. Fekete, J. Kovács, V. Rakosnikova, F. Votava, J. Lebl, Z. Pribilincova, S. M. Baumgartnet-Parzer, S. Riedl, F. Waldhauser, H. Frisch, M. Stopar-Obreza, C. Kržišnik, Tadej Battelino

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Objective: To analyze the mutational spectrum of steroid 21-hydroxylase (CYP21) and the genotype-phenotype correlation in patients with congenital adrenal hyperplasia (CAH) registered in the Middle European Society for Pediatric Endocrinology CAH database, and to design a reliable and rational approach for CYP21 mutation detection in Middle European populations. Design and methods: Molecular analysis of the CYP21 gene was performed in 432 CAH patients and 298 family members. Low-resolution genotyping was performed to detect the eight most common point mutations. High-resolution genotyping, including Southern blotting and sequencing was performed to detect CYP21 gene deletions, conversion point mutations or other sequence changes. Results: CYP21 gene deletion and In2 and Ile172Asn mutation accounted for 72.7% of the affected alleles in the whole study group. A good genotype-phenotype correlation was observed, with the exception of Ile172Asn and Pro30Leu mutations. In 37% of patients low resolution genotyping could not identify the causative mutation or distinguish homozygosity from hemizygosity. Using high-resolution genotyping, the causative mutation could be identified in 341 out of 348 analyzed patients. A novel mutation Gln315Stop was found in one simple virilising CAH (SV-CAH) patient from Austria. In the remaining seven patients polymorphisms were identified as the leading sequence alteration. The presence of elevated basal and ACTH-stimulated 17-hydroxyprogesterone, premature pubarche, advanced bone age and clitoral hypertrophy directly implicated Asn493Ser polymorphism in the manifestation of nonclassical- (NC) and even SV-CAH. Conclusions: By genotyping for the most common point mutations, CYP21 gene deletion/conversion and the 8 bp deletion in exon 3, it should be possible to identify the mutation in 94-99% of the diseased alleles in any investigated Middle European population. In patients with a mild form of the disease and no detectable mutation CYP21 gene polymorphisms should be considered as a plausible disease-causing mutation.

Original languageEnglish
Pages (from-to)99-106
Number of pages8
JournalEuropean journal of endocrinology
Volume153
Issue number1
DOIs
Publication statusPublished - Jul 1 2005

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Fingerprint Dive into the research topics of 'Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia'. Together they form a unique fingerprint.

  • Cite this

    Dolžan, V., Sólyom, J., Fekete, G., Kovács, J., Rakosnikova, V., Votava, F., Lebl, J., Pribilincova, Z., Baumgartnet-Parzer, S. M., Riedl, S., Waldhauser, F., Frisch, H., Stopar-Obreza, M., Kržišnik, C., & Battelino, T. (2005). Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia. European journal of endocrinology, 153(1), 99-106. https://doi.org/10.1530/eje.1.01944