New Compound Heterozygous Mutation in the <i>CYP17</i> Gene in a 46,XY Girl with 17α-Hydroxylase/17,20-Lyase Deficiency

Abstract

Background: 17α-Hydroxylase/17,20-lyase deficiency is caused by a defect of P450c17 which catalyzes both 17α-hydroxylase and 17,20-lyase reactions in adrenal glands and gonads. Results: In the present study, we analyzed the CYP17 gene in a Japanese patient with 17α-hydroxylase/17,20-lyase deficiency. The patient was a phenotypic girl and referred to us for right-sided inguinal hernia at the age of 4 years. Biopsy of the herniated gonad showed testicular tissue. The karyotype was 46,XY. At 6 years of age, hypertension was clearly recognized and the patient was diagnosed as having 17α-hydroxylase/17,20-lyase deficiency based on the clinical and laboratory findings. Analysis of the CYP17 gene revealed a compound heterozygous mutation. One mutation was an undescribed single nucleotide deletion at codon 247 in exon 4 (CTT to CT: 247delT) and the other was a missense mutation resulting in a substitution of His to Leu at codon 373 in exon 6 (CAC to CTC: H373L), which has been previously shown to abolish both 17α-hydroxylase and 17,20-lyase activities. The functional expression study of the 247delT mutant showed that this 247delT mutation completely eliminates both 17α-hydroxylase and 17,20-lyase activities. Conclusions: Together, these results indicate that the patient is a compound heterozygote for the mutation of the CYP17 gene (247delT and H373L) and that these mutations inactivate both 17α-hydroxylase and 17,20-lyase activities and give rise to clinically manifest 17α-hydroxylase/17,20-lyase deficiency.

Loss of Cytochrome P450 17A1 Protein Expression in a 17α-Hydroxylase/17,20-Lyase-Deficient 46,XY Female Caused by Two Novel Mutations in the CYP17A1 Gene

“…This condition is considered a disorder of sex development (DSD), which causes lack of virilization in 46, XY individuals [2]. Patients with 17OHD account for nearly 1% of all CAH cases, and at least 56 mutations have been described in the CYP17A1 gene [3][4][5][6][7]. The lack of adrenal 17α-hydroxylase activity leads to massive overproduction of mineralocorticoids (e.g., 11-deoxycorticosterone and corticosterone), promoting hypertension and hypokalemia [3].…”

Novel mutation of the CYP17 gene in two unrelated patients with combined 17α-hydroxylase/17,20-lyase deficiency: Demonstration of absent enzyme activity by expressing the mutant CYP17 gene and by three-dimensional modeling

“…The majority of mutations of the CYP17 gene reported to date have been associated with combined 17␣-hydroxylase/17,20-lyase deficiency [9][10][11][12][13][14][15][16][17][18][19][20][21], and most muta- tions have been localized within the coding region of the CYP17 [9][10][11][12][13][14][15][16][17][18][19][20][21]40]. Studies on naturally occurring and synthetic P450c17 mutants have shown that amino acid residues, which are predicted to participate in the heme-binding region or hydrophobic active site play a crucial role, although other residues may be also important in enzyme activity [15,21,24,29].…”

“…The human CYP17 is expressed in the adrenals and gonads and, therefore, genetic disorders of this gene affect both the adrenal and gonadal steroidogenesis [7,8]. Mutations of the CYP17 gene cause 17-hydroxylase/17,20-lyase deficiency (OMIM 202110) [9][10][11][12][13][14][15][16][17][18][19][20], which is a rare form of congenital adrenal hyperplasia (CAH) occurring in about 1% of all CAH patients. The impaired production of cortisol in zona fasciculata leads to hypersecretion of ACTH, which stimulates the synthesis of the weak mineralocorticoids 11-deoxycorticosterone (DOC) and corticosterone.…”

“…To date, approximately 50 different disease-causing genetic abnormalities of the CYP17 have been reported [9][10][11][12][13][14][15][16][17][18][19][20]. Genotype-phenotype correlations studies indicated a considerable variation in the clinical and biochemical presentation of the disorder [20].…”

“…It has been noted that the severity of clinical signs tended to be milder in cases with mutations, which retain partial enzyme activity compared to those cases, whose mutations were associated with a complete loss of enzyme activity. However, the phenotypic features appeared to be highly variable among affected individuals who had mutations that result in a complete loss of enzyme function [9][10][11][12][13][14][15][16][17][18][19][20][21]. Although the existence of isolated 17,20-lyase deficiency has been questioned, a few CYP17 mutations selectively affecting 17,20-lyase activity, including those which cause neutralization of positive charges in the redox partner-binding site have been described [21].…”