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A New Compound Heterozygous Mutation (W17X, 436+5GT) in the Cytochrome P450c17 Gene Causes 17-Hydroxylase/17,20-Lyase Deficiency

Department of Pediatrics, Gunma University School of Medicine, Maebashi, Gunma 371, Japan

Address all correspondence and requests for reprints to: Kanji Nagashima, M.D., Ph.D., Department of Pediatrics, Gunma University School of Medicine, 3–39-22 Showa-machi, Maebashi, Gunma 371, Japan.

A genetic disorder in cytochrome P450c17 results in 17-hydroxylase/17,20-lyase deficiency. In the present study, a Japanese patient with 17-hydroxylase/17,20-lyase deficiency underwent molecular analysis. The patient presented with complete female genitalia with a 46,XY karyotype, absent pubertal development, and hypertension. The exons and exon-intron boundaries of P450c17 genetic region were amplified and sequenced. DNA sequencing revealed a compound heterozygous mutation. One allele showed a G to A transition corresponding to a premature termination codon at tryptophane in codon 17 (W17X). The other allele showed a G to T substitution at the fifth nucleotide from the splice donor site in intron 2 (436+5GT). W17X was found in one allele of the father, and 436+5GT was found in one allele of the mother. A previous report presented a patient with 17-hydroxylase/17,20-lyase deficiency who was homozygous for W17X. However, the present case is a novel 436+5GT mutation.

Reverse transcription-PCR analysis using total ribonucleic acid isolated from the testes of the patient revealed that an intron 2 donor site mutation caused abnormal splicing, such that exon 2 was spliced with intron 2. Skipping the exon alters the translational reading frame of exon 3 and introduces a premature termination codon. In semiquantitative analysis, the majority of the transcript for 436+5GT skips exon 2.

The present findings indicate that in this patient, 17-hydroxylase/17,20-lyase deficiency was caused by the compound heterozygous mutation of exon and splice site mutation in cytochrome P450c17 gene.

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