5α-Reductase-2 gene mutations in the Dominican Republic .

Abstract

Male pseudohermaphroditism due to 5α-reductase deficiency was clinically and biochemically described in a large Dominican kindred of 23 families with 38 affected subjects in 1974. Recently, the 5α-reductase-2 gene defect in the large Dominican kindred was found to be due to a single base substitution of thymidine (TGG) for cytosine (CGG) on exon 5 of the 5α-reductase- 2 gene, causing a tryptophan replacement of arginine at amino acid 246 (R246W) of the enzyme. In the present report, affected subjects from four additional Dominican families were studied to determine whether they carried the same 5α-reductase- 2 gene defect as the large kindred, suggesting a common ancestry for the gene defect within this small country. Using single strand conformational polymorphism and DNA sequencing, two other mutations of the 5α-reductase-2 gene were found in affected subjects from two of the four families. A point mutation on exon 2 of the 5α-reductase-2 gene, in which substitution of adenine (GAC) for guanine (GGC) caused an aspartic acid replacement of glycine at amino acid 115 (G115D), was demonstrated in one of these families, and a substitution of adenine (AGT) for guanine (GGT) on exon 3 causing a serine replacement for glycine at amino acid 183 (G183S) was detected in the other family. Affected subjects from the two remaining families demonstrated the same exon 5 mutation of the 5α-reductase-2 gene as previously detected in the large Dominican kindred. The phenotypic and biochemical characteristics of the male pseudohermaphrodites were similar regardless of the genetic defect, except that one affected subject (C-VI-2) with the same exon 5 mutation as the large Dominican kindred had much more facial and body hair. Thus, the identification of multiple mutations in the 5α-reductase-2 gene in male pseudohermaphrodites from the Dominican Republic demonstrates a lack of common ancestry, as had been previously postulated.