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Molecular Genetic Analysis of Tunisian Patients with a Classic Form of 21-Hydroxylase Deficiency: Identification of Four Novel Mutations and High Prevalence of Q318X Mutation

Laboratoire de Génétique Humaine (M.K., R.M., F.M., L.B.J., M.R., H.C.), Faculté de Médecine de Tunis, 1006, Tunisie; and Laboratoire de Biochimie Endocrinienne (V.T., Y.M.), Institut National de la Santé et de la Recherche Médicale unité 329, Université de Lyon et Hôpital Debrousse, 69322 Lyon Cedex 05, France

Address all correspondence and requests for reprints to: Pr. Habiba Chaabouni, Laboratoire de Génétique Humaine, Faculté de Médecine de Tunis, 1006, Tunisie. E-mail: habiba.chaabouni{at}rns.tn.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders mainly due to defects in the steroid 21-hydroxylase (CYP21) gene. To determine the mutational spectrum in the Tunisian CAH population, the CYP21 active gene was analyzed in 51 unrelated patients using our cascade strategy (digestion by restriction enzyme, sequencing). All patients had a classical form of 21-hydroxylase deficiency. Mutations were detected in over 94% of the chromosomes examined. The most frequent mutation in the Tunisian CAH population was found to be Q318X, with large prevalence (35.3%), in contrast to 0.5–13.8% described in other series. Incidence of other mutations does not differ, as previously described: large deletions (19.6%), mutation in intron 2 (17.6%), and I172N (10.8%). Four novel mutations were found in four patients with the salt-wasting form. These four novel mutations include three point mutations that have not been reported to occur in the CYP21P pseudogene: R483W, W19X, 2669insC, and one small conversion of DNA sequence from exon 5 to exon 8. Our results have shown a good genotype/phenotype correlation in the case of most mutations. This is the first report of screening for mutations of 21-hydroxylase gene in the Tunisian population and even in the Arab population.

M.K. and V.T. have contributed equally to this work and could be considered as first authors.

Abbreviations: CAH, Congenital adrenal hyperplasia; CYP21, steroid 21-hydroxylase gene; 21-OHD, 21-hydroxylase deficiency; RFLP, restriction fragment length polymorphism; SV, simple virilizing; SW, salt wasting.

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