Steroid 5α‐reductase 2 deficiency: virilization in early infancy may be due to partial function of mutant enzyme

Forti, Gianni; Falchetti, Alberto; Santoro, Salvatore; Davis, Dana; Wilson, Jean D.; Russell, David W.

doi:10.1046/j.1365-2265.1996.673496.x

Cited by 24 publications

(20 citation statements)

References 6 publications

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“…In our study, the enzymatic activity was retained in about 40% with the p.G203S mutation. It was reported that the SRD5A2 missense mutation retaining 3–15% of enzymatic activities was associated with partial male external genitalia [20]. Therefore, the p.G203S mutation was also associated with masculinization of the external genitalia.…”

Section: Discussionmentioning

confidence: 99%

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

et al. 2011

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Objective: To investigate the functional change of SRD5A2 gene mutations identified in patients with 5α-reductase type 2 deficiency. Patients and Methods: Three unrelated subjects born with ambiguous genitalia were included. All patients were initially reared as girls, but they gradually exhibited variable degrees of virilization at puberty without breast development, followed by a change of gender role. Sequencing analysis of the SRD5A2 gene was performed and enzymatic activities of 5α-reductase type 2 were assessed. Results: Three compound heterozygous mutations in the SRD5A2 gene were identified: patient 1 with p.G203S/ c.655delT, patient 2 with p.Q6X/p.G203S, and patient 3 with p.G203S/c.755_756insT. Heterozygosity for the p.V89L polymorphism was also found in patients 2 and 3. The c.655delT mutation led to a complete loss of the enzymatic activity, whereas mutants p.G203S and c.755_756insT resulted in a reduction of the enzymatic activities by 60 and 90%, respectively. Conclusion: Two frameshift heterozygous mutations, c.655delT and c.755_756insT, led to a dramatic reduction in 5α-reductase activity, and the latter had not been reported previously. In addition, the heterozygous mutation (p.G203) identified in the 3 patients presumably suggests a founder effect in the Chinese population and may explain the similarity in phenotype among the patients.

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Section: Discussionmentioning

confidence: 99%

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

et al. 2011

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“…Mais de 40 mutações diferentes já foram descritas, compreendendo em sua maioria mutações de ponto do tipo missense ou nonsense e, mais raramente, mutações que afetam o mecanismo de splicing, mutações frameshift (que alteram a fase de leitura) ou deleções completas do gene (8,13,(15)(16)(17)(18)(19)(20). Segundo Thigpen e cols.…”

Section: Discussionunclassified

“…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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“…These cases were all considered to be girls at birth (6,8,10). The mutation has even been reported in a heterozygous form in two cases regarded as presumed compound heterozygotes, one in an Afro-American and the other in an American Caucasian proband (1).…”

Section: Resultsmentioning

confidence: 99%

Molecular Characterization of 5α-Reductase Type 2 Deficiency and Fertility in a Swedish Family1

Nordenskjöld¹,

Ivarsson

1998

The Journal of Clinical Endocrinology &Amp; Metabolism

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The molecular background of 5␣-reductase type 2 deficiency was investigated in a Swedish family with no known consanguinity and in which the affected males were fertile. The three male siblings were born with ambiguous external genitalia, and the diagnosis of 5␣-reductase deficiency was established at the ages of 16, 14, and 10 yr, respectively. All three siblings underwent surgery for hypospadias repair. At least two of the brothers are demonstrably fertile. Molecular analysis showed the three brothers to be compound heterozygotes, carrying two different mutations in exon 4 of the 5␣-reductase type 2 gene. The two mutations (G196S and H231R) have been described previously and reported to give rise to partially functioning enzymes, which may explain the milder phenotype and perhaps the fertility in the preset three patients. (J Clin Endocrinol Metab 83: 3236 -3238, 1998)

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Steroid 5α‐reductase 2 deficiency: virilization in early infancy may be due to partial function of mutant enzyme

Cited by 24 publications

References 6 publications

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

A Novel SRD5A2 Mutation with Loss of Function Identified in Chinese Patients with Hypospadias

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

Molecular Characterization of 5α-Reductase Type 2 Deficiency and Fertility in a Swedish Family1

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