Seventeen alpha-
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 17alpha-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 17alpha-
hydroxylase/
17,20-lyase deficiency syndrome. Here, we describe two phenotypically and hormonally affected Italian patients with 17alpha-
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 17alphahydroxylase 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.