This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Menassa, R. Articles by Morel, Y. Search for Related Content PubMed PubMed Citation Articles by Menassa, R. Articles by Morel, Y. Related Collections Adrenal and Hypertension Pediatric Endocrinology

p.H62L, a Rare Mutation of the CYP21 Gene Identified in Two Forms of 21-Hydroxylase Deficiency

Laboratoire d’Endocrinologie Moléculaire et Maladies Rares (R.M., V.T., Y.M.), Centre de Biologie et de Pathologie Est, 69677 Bron, France; Centre de Pédiatrie (F.D.), Centre Hospitalier Universitaire de Tours, 37044 Tours, France; Centre de Pédiatrie (C.B.-M.), Groupe Hospitalier Cochin St. Vincent de Paul, 75014 Paris, France; Service de Pédiatrie-Néonatologie (J.P.B.), Centre Hospitalier, 85000 La Roche sur Yon, France; and Endocrinologie (M.C.), Centre de pédiatrie Hôpital Jeanne de Flandre, 59037 Lille, France

Address all correspondence and requests for reprints to: Véronique Tardy, Laboratoire d’Endocrinologie Moléculaire et Maladies Rares, Centre de Biologie et de Pathologie Est, 69677 Bron Cedex, France. E-mail: veronique.tardy{at}chu-lyon.fr.

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.

This article has been cited by other articles:

				F. C. Soardi, M. Barbaro, I. F. Lau, S. H. V. Lemos-Marini, M. T. M. Baptista, G. Guerra-Junior, A. Wedell, S. Lajic, and M. P. de Mello Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2416 - 2420. [Abstract] [Full Text] [PDF]