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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.

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