Mutations In SRD5A2 Gene Research Articles

Two Novel Mutations of SRD5A2 Gene in Indonesian Siblings with Clinical 5-Alpha-Reductase Deficiency

Steroid 5-alpha-reductase 2 deficiency is an autosomal recessive disorder with clinical spectrum ranges from a male phenotype with hypospadia to a female phenotype with normal wolffian structures. Over 50 different mutations of SRD5A2 gene has been described in affected patients and several mutations were detected in specific populations. DNAs of two 46,XY DSD Indonesian siblings, aged 13 and 18 years old, with clinically suspected of 5-alpha-reductase deficiency and their mother were analysed for molecular defects of SRD5A2 gene. Different from other reports, in our series three mutations were found in each patient. Two novel mutations were detected in these patients and their mother, which are p.Gly34fs and c.699-1G>T. The other mutation detected was c.680G>A or p.Arg227Gln, which commonly described in Far East Asian population. Whether the p.Arg227Gln mutation is considered a polymorphism or a mutation in Indonesian population warrants further study.

Molecular Diagnosis of 46,XY DSD and Identification of a Novel 8 Nucleotide Deletion in Exon 1 of the SRD5A2 Gene

Phenotypic presentation of 46,XY DSD depends on the underlying defects. Defect in androgen action on the target tissues or production of active metabolite share common morphological features. Molecular study may help differentiating these abnormalities with precision. Mutational analysis of androgen receptor (AR) and SRD5A2 genes was performed in 29 patients with 46,XY DSD, by PCR-SSCP. The amplicons that showed an aberrant migration in SSCP were subjected to sequencing. Interestingly, six patients from 4 unrelated families (a pair of sibs, uncle/nephew and other two isolated) were identified with mutations in SRD5A2 gene. In five patients p.R246Q missense mutation was detected, of which four were homozygous and one was compound heterozygous: g.80_87delT CGCGAAG (p.A27fsX132) and p.R246Q. Another patient with isolated micropenis harbored a heterozygous p.G196S missense mutation. No AR gene mutation was detected. In conclusion, our study suggests that p.R246Q mutation is common amongst patients with SRD5A2 gene defect from the Northern states of India. Also, it records a novel deletion in exon 1 of SRD5A2 gene in a patient with severe hypospadias.

Differences in Testicular Development Between 5α-Reductase 2 Deficiency and Isolated Bilateral Cryptorchidism

We demonstrated that infertility develops in most patients with steroid 5alpha-reductase 2 deficiency. We compared the testicular histopathology of boys with steroid 5alpha-reductase 2 deficiency to that of boys with isolated bilateral cryptorchidism. Testes with steroid 5alpha-reductase 2 deficiency lacked spermatocytes but had Ad spermatogonia and a normal germ cell count. In contrast, bilateral cryptorchid testes had severe germ cell depletion and the majority lacked Ad spermatogonia. In patients with steroid 5alpha-reductase 2 deficiency the impaired second step of germ cell maturation results in defective transformation of spermatogonia into spermatocytes. The position of the undescended testis appears to have no major pathological impact on the development of germ cells in patients with steroid 5alpha-reductase 2 deficiency.

Micropenis and the 5alpha-reductase-2 (SRD5A2) gene: mutation and V89L polymorphism analysis in 81 Japanese patients.

The 5alpha-reductase-2 encoded by the SRD5A2 gene plays a critical role in male sex differentiation by converting testosterone into 5alpha 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 SD 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.

Phenotypic classification of male pseudohermaphroditism due to steroid 5α-reductase 2 deficiency

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( > 50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.