p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency.
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Menassa R, Tardy V, Despert F, Bouvattier-Morel C, Brossier JP, Cartigny M, Morel Y
p.H62L, a rare mutation of the CYP21 gene identified in two forms of 21-hydroxylase deficiency.
J Clin Endocrinol Metab. 2008 May;93(5):1901-8. doi: 10.1210/jc.2007-2701. Epub 2008 Mar 4.
- PubMed ID
- 18319307 [ View in PubMed]
- Abstract
CONTEXT: Steroid 21-hydroxylase deficiency is the most common enzymatic defect causing congenital adrenal hyperplasia with good genotype/phenotype relationships for common mutations. To determine the severity of rare mutations is essential for genetic counseling and better understanding of the structure-function of the cytochrome P450c21. OBJECTIVE: The p.H62L mutation was the most frequent of 60 new mutations detected in 2900 steroid 21-hydroxylase deficiency patients, either isolated or associated on the same allele with a mild mutation (p.P453S, p.P30L, or partial promoter). Because phenotypes seemed to differ between patients with isolated or associated p.H62L, a detailed phenotype description and functional studies were performed. RESULTS: Regarding phenotype, patients with isolated p.H62L had a nonclassical form, whereas patients with the association p.H62L + mild mutation had a simple virilizing form. Functional studies showed that p.H62L reduced the conversion of the two substrates, progesterone and 17-hydroxyprogesterone, in the same way as the mild p.P453S; the association p.H62L + p.P453S decreased enzymatic activity more strongly while conserving residual activity at a level intermediate between p.P453S and p.I172N. This suggested that p.H62L was a mild mutation, whereas a synergistic effect occurred when it was associated. Analysis of p.H62L in a three-dimensional model structure of the CYP21 protein explained the observed in vitro effects, the H62 being located in a domain implied in membrane anchoring. CONCLUSION: According to phenotype and functional studies, p.H62L is a mild mutation, responsible for a more severe phenotype when associated with another mild mutation. These data are important for patient management and genetic counseling.