A novel missense (R80W) mutation in 17-β-hydroxysteroid dehydrogenase type 3 gene associated with male pseudohermaphroditism

Objective: Deficit of the testosterone converting enzyme 17-beta-hydroxysteroid dehydrogenase (17 beta-HSD) has been shown to be responsible for male pseudohermaphroditism (MPH). Mie analysed the gene encoding 17 beta-HSD type 3 (17 beta-HSD3) in a patient with MPH. Methods: Mie studied a 46, XY new-born diagnosed as having MPR. The child also had other congenital disorders, including a giant omphalocele and Fallot's tetralogy, and died of post-surgical complications at age 4.5 months. Basal hormonal levels, and after human chorionic gonadotrophin stimulation, suggested a deficiency in 17 beta-HSD as the biochemical defect underlying this MPH. PCR amplification and subsequent sequencing of all coding exons of the 17 beta-HSD3 gene were performed on genomic DNA from the patient and both parents. Messenger RNA was extracted from the patient's testis and 17 beta-HSD3 cDNA was synthesized, PCR amplified and sequenced. Results: Sequencing revealed the presence of a homozygous missense mutation (R80W) in exon 3 of the 17 beta-HSD3 gene, which was also present in single doses in both parents, in accordance with the recessive inheritance of the defect. No other mutation was found, and cDNA sequencing confirmed correct synthesis and processing of 17 beta-HSD3 mRNA. Conclusions: Confirming the abnormal Delta 4-androstenedione/testosterone ratios that suggested 17 beta-HSD deficiency, a homozygous missense mutation in the gene coding for this enzyme was identified in the patient with MPH. This study adds further genetic evidence to the role of 17 beta-HSD3 in male sexual development. There is no evidence supporting the association of this mutation in 17 beta-HSD3 with the congenital malformations other than MPH present in the child.