Molecular analysis of 5α‐reductase type 2 gene in eight unrelated egyptian children with suspected 5α‐reductase deficiency: prevalence of the G34R mutation

Mazen, Inas; Gad, Yehia Z.; Hafez, Mona; Sultan, Charles; Lumbroso, Serge

doi:10.1046/j.1365-2265.2003.01763.x

Cited by 57 publications

(56 citation statements)

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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: 98%

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: 98%

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 freqüência elevada de heterozigotos compostos sugere que a freqüência de portadores na população em geral pode ser alta, o que explicaria a recorrência de determinadas mutações em afetados não consangüí-neos. Por outro lado, a recorrência de mutações idênti-cas em diferentes grupos étnicos e de regiões geográfi-cas distintas tem sugerido a existência de regiões hot spots no gene; em outros casos, mutações similares dentro do mesmo grupo étnico seriam derivadas de mutações presentes em ancestrais comuns (8,13,21).…”

Section: Discussionunclassified

Deficiência de 5alfa-redutase tipo 2: experiências de Campinas (SP) e Salvador (BA)

Hackel

Oliveira

Toralles

et al. 2005

Arq Bras Endocrinol Metab

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RESUMOObjetivo: Apresentar a experiência relativa a pacientes com deficiência da enzima 5α-redutase tipo 2 provenientes de três serviços distintos no Brasil. Casuística e métodos: Foram incluídos 25 pacientes com sinais clínicos e hormonais de deficiência da 5α-redutase 2 pertencentes a 23 famílias, 15 oriundas da Bahia, 7 de São Paulo e 1 de Minas Gerais. Foram avaliados dados clínicos, hormonais e moleculares. A análise molecular dos 5 éxons do gene SRD5A2 foi feita por meio da técnica de PCR, seguida de seqüenciamento automático ou manual. Resultados: Em 10 famílias havia mutações no gene SRD5A2 em homozigose (5 com G183S, 2 com R246W, 1 com G196S, 1 com del642T, 1 com 217_218insC) e em 3 em heterozigose composta (1 com Q126R/IVS3+1G>A, 1 com Q126R/del418T e 1 com Q126R/G158R); em 3 casos os afetados eram heterozigotos, apresentando apenas uma mutação deletéria (1 com G196S, 1 com A207D e 1 com R246W). Em 7 casos não foram detectadas anormalidades ao seqüenciamento. Observou-se maior freqüência da G183S em pacientes miscigenados (Afro-Euro-Brasileiros) oriundos da Bahia. Os achados clínicos e hormonais não diferiram entre os casos com e sem mutação, à exceção da freqüência de consangüinidade e da maior gravidade da ambigüidade genital nos primeiros. Conclusões: Os resultados encontrados salientam a importância da investigação molecular para o diagnóstico dessa doença, ressaltando o achado de uma mutação bastante freqüente em nosso meio (G183S), especialmente em pacientes miscigenados oriundos da Bahia, e a descrição de mutações que até o momento só foram relatadas em pacientes brasileiros. Objective: To report the experience regarding patients with steroid 5α-reductase type 2 deficiency from three different clinical services in Brazil. Casuistic and methods: Twenty five patients with clinical and hormonal features of 5α-reductase deficiency from 23 families (15 from Bahia, 7 from São Paulo and 1 from Minas Gerais) were included in this study. Clinical, hormonal and molecular data were evaluated. The molecular analysis of the five exons of the SRD5A2 gene was done by automatic or manual sequencing of PCR products. Results: In ten families, SRD5A2 mutations were found in homozygosis (5 with G183S, 2 with R246W, 1 with G196S, 1 with del642T, 1 with 217_218insC), in three in compound heterozygosis (1 with Q126R/IVS3+1G>A, 1 with Q126R/del418T, 1 with Q126R/G158R) while other three were heterozygous, with only one deleterious mutation (1 with G196S, 1 with A207D, and 1 with R246W). In seven cases, no sequencing abnormalities were detected. The G183S substitution was the most frequently found among miscigenated patients (Afro-Euro-Brazilians) from Bahia. Hormonal and clinical findings did not differ between patients with or without mutations, exception made to a higher frequency of consanguinity and greater severity of genital ambiguity in the first group. Conclusions: Our results reinforce the importance of molecular investigation for the diagnosis of this disease and point out to the finding of a very frequent mu...

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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 analysis of 5α‐reductase type 2 gene in eight unrelated egyptian children with suspected 5α‐reductase deficiency: prevalence of the G34R mutation

Abstract: Among eight unrelated Egyptian children with 5alpha-reductase deficiency, the G34R mutation was identified in five patients. The high consanguinity rate in Egypt suggests a common ancestor with a founder gene effect in cases of G34R mutation.

Cited by 57 publications

References 26 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

Deficiência de 5alfa-redutase tipo 2: experiências de Campinas (SP) e Salvador (BA)

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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