The 5α-reductase-2 encoded by the SRD5A2 gene plays a critical role in male sex differentiation by converting testosterone into 5α dihydrotestosterone in the peripheral target tissues. In this study, we examined the SRD5A2 gene in 81 Japanese patients with micropenis (age, 0-14 yr; median, 7 yr) whose stretched penile lengths were between -2.5 SD and -2.0 so in 39 patients (age, 0-13 yr; median, 8 yr) and below -2.5 SD in 42 patients (age, 0-14 yr; median, 6 yr), together with 100 control males (50 boys and 50 fertile adult males). Mutation analysis was performed for exons 1-5 and their flanking introns by denaturing HPLC and direct sequencing, revealing Y26X/R227Q in an 11-yr-old boy with a penile length of -2.6 SD, G34R/R227Q in a 9-yr-old boy with a penile length of -3.6 SD, and R227Q/R227Q in a 3-yr-old boy with a penile length of -2.4 SD, together with heterozygous R227Q in a control boy and a fertile adult male. Polymorphism analysis was carried out for the most frequent V89L known to reduce the enzyme activity by approximately 30% in 78 patients, except for the three patients with SRD5A2 mutations, and in the 100 control males by direct sequencing, showing that allele and genotype frequencies were similar between 78 patients with micropenis below -2.0 SD or 40 patients with micropenis below -2.5 SD and the 100 control males, the 50 boys, or the 50 fertile adult males, with no statistically significant differences. The results suggest that, in Japanese patients, micropenis can be caused by SRD5A2 gene mutations, especially by R227Q which has been shown to retain approximately 3.2% of normal enzyme activity and appears relatively frequent in Asian populations, and that V89L polymorphism is unlikely to raise the susceptibility to the development of micropenis.
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