Clinical and molecular characterization of 5α-reductase type 2 deficiency due to mutations (p.Q6X, p.R246Q) in <i>SRD5A2</i> gene

Abstract

Abstract. Early diagnosis and optimal management for steroid 5α-reductase type 2 deficiency (5α-RD2) patients are major challenges for clinicians and mutation analysis for the 5α-reductase type 2 (SRD5A2) gene is the golden standard for the diagnosis of the disease. In silico analysis of this enzyme has not been reported due to the lack of appropriate model. Moreover, the histological and pathological changes of the gonads are largely unknown. In the present study, a 5α-RD2 patient born with abnormal external genitalia was studied and mutation analysis for SRD5A2 gene was conducted. Moreover, we constructed the homology modeling of 5α-reductase using SWISS-MODEL, followed by the molecular docking study. Furthermore, immunohistochemical staining of Ki67 for the testes tissue was conducted to investigate the potential pathological characteristics. The patient had male (46, XY) chromosomes but presented female characteristics, and the mutation analysis identified a heterozygotes mutation (p.Q6X, p.R246Q) in SRD5A2 gene. In silico analysis elucidated the potential effect of the mutation on enzyme activity. Immunohistochemical staining for the excised testes showed that 30%-50% of the germ cells were Ki67 positive, which indicated the early neoplastic potential. In conclusion, we analyzed the genotype-phenotype correlations of 5α-RD2 caused by a heterozygotes mutation (p.Q6X, p.R246Q). Importantly, we conducted the homology modeling and molecular docking for the first time, which provided a homology model for further investigations. Immunohistochemical results suggested gonadectomy or testis descent should be performed early for 5α-RD2 patient, as delayed treatment would have maintained the testes in a tumorigenic condition.

Insight into the Possible Formation Mechanism of the Intersex Phenotype of Lanzhou Fat-Tailed Sheep Using Whole-Genome Resequencing

“…Functional enrichment analysis revealed significant entries for the androgen biosynthesis processes and follicle stimulating hormone responses, including SRD5A2, SRD5A3, and PAWR genes. Among them, mutations of the SRD5A2, which were closely related to testicular decline, could affect the formation of the urethra and external genitalia, leading to hypoplasia of the male reproductive organs [35]. Therefore, polymorphisms of the SRD5A2 gene may be a key point leading to intersexuality in sheep.…”

“…Functional enrichment of the sequencing data for intersex sheep and normal sheep populations (including Tan sheep) did not find significant entries related to gonadal development or sex hormone metabolisms. A previous study reported that testicular tissue dysplasia was a key cause of human gender developmental disorders [35]. Additionally, the excessive synthesis of estrogen in vivo also affected the formation and development of female reproductive organs.…”

Galangin and Pinocembrin from Propolis Ameliorate Insulin Resistance in HepG2 Cells via Regulating Akt/mTOR Signaling

“…The three-dimensional (3D) structure of the human IR (PDB ID: 2HR7) was downloaded from RCSB Protein Data Bank ( http://www.rcsb.org/pdb/home/home.do ) [ 21 ]. The 2D structures of the galangin and pinocembrin were drawn by ChemBioDraw Ultra 14.0 and converted to 3D structures by the ChemBio3D Ultra 14.0 package [ 22 ]. The AutoDockTools 1.5.6 package [ 23 , 24 ] was employed to generate the docking input files.…”

“…For Vina docking, the default parameters were used if it was not mentioned. The best-scoring pose as judged was chosen by the Vina docking score and visually analyzed using PyMoL 1.7.6 software ( http://www.pymol.org/ ) [ 22 ].…”

Histological analysis of testes in patients with 5 alpha-reductase deficiency type 2: Comparison with cryptorchid testes in patients without endocrinological abnormalities and a review of the literature

“…Theoretically, the testes of the affected 46,XY individuals are expected to differentiate normally and indeed, several reports have revealed intact histology of the testes in 5αRD patients during infantile and toddler periods ( 13 , 14 ); however, almost all patients suffer from azoospermia or oligospermia during adulthood, indicating that deterioration of spermatogenesis likely occurs after infantile and toddler periods ( 13 , 14 , 15 , 16 ). Although there is evidence to show that the lack of 5 alpha-reductase type 2 activity itself affects germ cell numbers in 5αRD patients ( 14 , 16 ), accompanying cryptorchidism has also been observed to adversely affect spermatogenesis, suggesting that the underlying mechanisms of defective spermatogenesis are complex.…”