Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency

Hiort, Olaf; Willenbring, Holger; Albers, Norbert; Hecker, Wolfgang; Engert, J.; Dibbelt, L.; Sinnecker, G. H. G.

doi:10.1007/bf01955179

Cited by 60 publications

(52 citation statements)

References 25 publications

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“…Results showed a significant elevation of serum T/DHT ratio, indicating that the testes of the patient were able to secret T and the conversion from T to DHT was suppressed. However, the post hCG stimulation T/DHT ratios varies according to age and the severity of the enzyme defects, and the false-negative results [8][9][10][11]. There are patients that diagnosed with 5α-RD2 by gene mutational analysis even they had normal T/DHT ratio after the hCG stimulation, which means the precise diagnosis was not accomplished for this patient [9,12].…”

Section: Discussionmentioning

confidence: 95%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 95%

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

et al. 2018

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“…A specific role of the 5a-reductase type 1 enzyme in male sexual differentiation has not been demonstrated. In contrast, several mutations have been described in the type 2 enzyme in patients with defective virilisation (34,42,44). The underlying gene has been localised on chromosome 2p23 and is divided into 5 exons.…”

Section: Late Steps Of Androgen Biosynthesismentioning

confidence: 99%

“…The underlying gene has been localised on chromosome 2p23 and is divided into 5 exons. In 5a-reductase deficiency, DHT formation is severely diminished (44). However, testosterone levels are normal or even elevated.…”

Section: Late Steps Of Androgen Biosynthesismentioning

confidence: 99%

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The molecular basis of male sexual differentiation

Hiort

Holterhus

2000

European Journal of Endocrinology

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Male sexual differentiation is the result of complex mechanisms involving developmental genetics and endocrinology. Formation of the bipotential gonads and subsequently the testes is dependent on a series of sex chromosome-linked and autosomal genes. The testes secrete both peptide and steroid hormones essential for the formation of internal and external genitalia. Hormone action is mediated via specific receptors, functioning as transcription regulators. Disruption of these genetic events leads to sexual dimorphism involving external and internal genitalia, and may also interfere with the development of other organs.

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“…This can occur to such an extent that affected individuals change their sex of rearing from female to male (1,3,7,8). Furthermore, these individuals can show normal DHT-concentrations (1) and normal T/DHT-ratios (4,9) in serum. Additionally, testosterone treatment can lead to an increase of DHT-levels up to normal values (1,10).…”

Section: Introductionmentioning

confidence: 99%

Isoenzyme type 1 of 5alpha-reductase is abundantly transcribed in normal human genital skin fibroblasts and may play an important role in masculinization of 5alpha-reductase type 2 deficient males

et al. 2005

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Objective: 5alpha-reductase enzymes reduce testosterone (T) to the most potent androgen dihydrotestosterone (DHT). Two isoenzymes are known to day. While the type 2-enzyme (5RII) is predominantly expressed in male genital tissues and mutations are known to cause a severe virilization disorder in genetic males, the role of the type 1-enzyme (5RI) in normal male androgen physiology is unclear. We investigated whether 5RI is transcribed in normal male genital skin fibroblasts (GSFs) and if the transcription is regulated by age or by androgens themselves. Methods: GSF from 14 normally virilized males of different ages, ranging from 8 months to 72 years, obtained at circumcision were cultured. Total RNA was isolated after incubation for 48 h with 100 nM T or without androgens. Each sample was amplified in triplicate by real-time PCR with porphobilinogen desaminase as a housekeeping gene used for semiquantification. Selected cultures were analyzed after incubation with 10 and 100 nM T and 1 and 100 nM DHT for 24, 48 and 120 h. Results: 5RI was transcribed in all investigated samples with a 4.5-fold variability in the mRNA concentration of different individuals. However, neither age-related regulation nor significant influence of T or DHT on the transcription rate was discovered. Conclusion: Since 5RI is abundantly transcribed in GSFs, we hypothesize that this isoenzyme may play important roles in the androgen physiology of normally virilized males and may contribute to masculinization in 5RII-deficient males at the time of puberty.European Journal of Endocrinology 152 875-880

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Molecular genetic analysis and human chorionic gonadotropin stimulation tests in the diagnosis of prepubertal patients with partial 5α-reductase deficiency

Abstract: While abnormal T/DHT ratios were identified with both hCG protocols in the patients, prolonged stimulation lead to higher T values and to higher T/DHT rations, and hence to a better discrimination of pathologic results.

Cited by 60 publications

References 25 publications

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

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

The molecular basis of male sexual differentiation

Isoenzyme type 1 of 5alpha-reductase is abundantly transcribed in normal human genital skin fibroblasts and may play an important role in masculinization of 5alpha-reductase type 2 deficient males

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