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Combined 17-Hydroxylase/17,20-Lyase Deficiency Caused by Phe93Cys Mutation in the CYP17 Gene

Division and Research Unit of Endocrinology (A.D.C.) and Departments of Medical Genetics (M.S., M.R.P., A.S.) and Clinical Pathology (A.D.G.), Istituto di Ricovero e Cura a Carattere Scientifico Ospedale "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo, Italy; Department of Pediatric Endocrinology/Diabetology (A.B.-L.), University Children’s Hospital, CH-8032 Zurich, Switzerland; and Unit of Analitical Chemistry (M.P.), Azienda Ospedaliera O.I.R.M.-S.Anna, 10126 Turin, Italy

Address all correspondence and requests for reprints to: Dr. Alfredo Di Cerbo, Division and Research Unit of Endocrinology, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale "Casa Sollievo della Sofferenza," 71013 San Giovanni Rotondo (Foggia), Italy. E-mail: adicerb{at}tin.it

Abstract

Seventeen -hydroxylase/17,20-lyase deficiency is a rare, autosomal recessive form of congenital adrenal hyperplasia not linked to human leukocyte antigen and characterized by the coexistence of hypertension caused by the hyperproduction of mineralocorticoid precursors and sexual abnormalities, such as male pseudohermaphroditism and sexual infantilism in female, due to impaired production of sex hormones. Both 17-hydroxylase and 17,20-lyase reactions are catalyzed by a single polypeptide, cytochrome P450c17 (CYP17), which is encoded by the CYP17 gene located on chromosome 10q24-q25. Mutations in the CYP17 gene have been recognized to cause the 17-hydroxylase/17,20-lyase deficiency syndrome.

Here, we describe two phenotypically and hormonally affected Italian patients with 17-hydroxylase/17,20-lyase deficiency. The family history revealed consanguinity of the parents. Linkage and haplotype analyses using microsatellites on chromosome 10q24-q25 demonstrated that the two affected individuals were homozygous at these loci. The mutation screening of the CYP17 gene identified a new Phe93Cys missense mutation in exon 1. The amino acid substitution is located in a highly conserved region of the protein and is not a polymorphism because it is not present in one hundred normal alleles. In vitro functional studies showed that the Phe93Cys mutated CYP17 retains only 10% of both 17hydroxylase and 17,20-lyase activities, according to the severe phenotype. Our results shed more light on the structure-function relationship of the CYP17 protein indicating that Phe 93 is crucial for both enzymatic activities.

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