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The Identification of 5-Reductase-2 and 17ß-Hydroxysteroid Dehydrogenase-3 Gene Defects in Male Pseudohermaphrodites from a Turkish Kindred¹

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cornell University Medical College (S.C., Y.-S.Z., L.-Q.C., Q.L., M.D.K., J.I.-M.), New York, New York 10021; Medical Service, Veterans Administration Medical Center (S.A.), East Orange, New Jersey 07019; and Children’s Hospital Oakland Research Institute (C.H.L.S.), Oakland, California 94609

Address all correspondence and requests for reprints to: Dr. Julianne Imperato-McGinley, Division of Endocrinology, Diabetes, and Metabolism, New York Hospital-Cornell Medical Center, 1300 York Avenue, Box 149, Room F-263, New York, New York 10021.

Male pseudohermaphroditism (MPH) is characterized by incomplete differentiation of male genitalia in the presence of testicular tissue. Enzymatic defects involving androgen synthesis or action are causes of MPH. We studied the molecular genetics of a large isolated inbred Turkish kindred with MPH due to either 5-reductase-2 (SRD5A2) or 17ß-hydroxysteroid dehydrogenase-3 (17ßHSD3) gene defects. Using single strand DNA conformational polymorphism analysis and DNA sequencing, a new mutation in exon 5 of SRD5A2 gene was detected in certain male pseudohermaphrodites from this kindred. This single base deletion (adenine) resulted in a frame shift at amino acid position 251 resulting in the addition of 23 amino acids at the carboxyl-terminal of this 254-amino acid isozyme. Transfection expression of the mutant isozyme in CV1 cells showed a complete loss of enzymatic activity in the conversion of [¹⁴C]testosterone to dihydrotestosterone, without a change in the messenger ribonucleic acid level compared to that of the wild-type isozyme. Analysis of the 17ßHSD3 gene in other male pseudohermaphrodites from this kindred revealed a single point mutation (GA) at the boundary between intron 8 and exon 9, disrupting the splice acceptor site of exon 9.

In this kindred, in addition to the identification of male pseudohermaphrodites with either a homozygous SRD5A2 or 17ßHSD3 gene defect, other male pseudohermaphrodites were found to be genetically more complex: e.g. homozygous for the SRD5A2 defect and heterozygous for the 17ßHSD3 defect, or homozygous for the 17ßHSD3 defect and heterozygous for the SRD5A2 defect. Also, phenotypically normal carriers were identified with either one or both gene defects.

Homozygous male pseudohermaphrodites with SRD5A2 or 17ßHSD3 gene defects were phenotypically distinguishable by the presence of mild gynecomastia in the latter. Hormone data were consistent with the particular homozygous gene defect. In summary, we show 1) the novel existence of two gene defects, SRD5A2 and 17ßHSD3, each causing MPH within a large isolated Turkish kindred; 2) that the two defects segregate independently and may be inherited from two different progenitors; and 3) analysis of a new mutation in exon 5 of SRD5A2 gene, supporting the functional importance of the carboxyl-terminal of 5-reductase-2 isozyme.

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