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

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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.

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