Mutations of the 5α‐reductase Type 2 gene in eight Mexican patients from six different pedigrees with 5α‐reductase‐2 deficiency

Canto, Patricia; Vilchis, Felipe; Chávez, Bertha; Mutchinick, Osvaldo M.; Imperato‐McGinley, Julianne; Pérez‐Palacios, Gregorio; Ulloa‐Aguirre, Alfredo; Méndez, Juan Pablo

doi:10.1046/j.1365-2265.1997.800904.x

Cited by 78 publications

(36 citation statements)

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“…The SRD5A2 gene analyses revealed four different mutations in 6 patients, all of which have earlier been reported as pathologic [11,12,13,14]. Patients 1 and 2 were sisters, and showed a homozygous deletion of thymine at nucleotide position c.655 of exon 4 (c.655delT).…”

Section: Resultsmentioning

confidence: 95%

Clinical Characterization and Analysis of the <i>SRD5A2 </i>Gene in Six Korean Patients with 5α-Reductase Type 2 Deficiency

Ko¹,

Cheon²,

Kim

et al. 2010

Horm Res Paediatr

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Aims: The aim of this study was to perform a 5α-reductase type 2 gene (SRD5A2) analysis in 6 Korean patients with external genitalia ranging from predominantly female to male in whom 5α-reductase type 2 deficiency was suspected. Patients: Six patients from five unrelated families participated, and all of their parents were non-consanguineous. Three patients presented with ambiguous genitalia at birth, and 2 were referred owing to delayed puberty. The other patient was presented incidentally during an operation for inguinal hernia. Basal and post-human chorionic gonadotropin-stimulated serum testosterone and dihydrotestosterone levels were determined, but neither the levels nor ratio yielded enough information for differential diagnosis. Confirmative diagnosis was achieved by SRD5A2 gene analysis. Results: Four different pathologic mutations were identified. All have already been reported, and are located in exon 1 (p.Q6X), exon 4 (p.G203S and c.655delT), and exon 5 (p.R246Q). p.R246Q was the most frequently identified mutation in our study, and c.655delT has been detected only in Korean patients to date. Conclusion: The molecular analysis is the most reliable method for a correct diagnosis of 5α-reductase type 2 deficiency. Identification of mutations also enables genetic counseling for families at risk.

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Section: Resultsmentioning

confidence: 95%

Clinical Characterization and Analysis of the <i>SRD5A2 </i>Gene in Six Korean Patients with 5α-Reductase Type 2 Deficiency

Ko¹,

Cheon²,

Kim

et al. 2010

Horm Res Paediatr

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“…Ser and Gly115 ? Asp, have been found predominantly in subjects from Latin American countries such as Brazil, Mexico, and Dominican Republic (Thigpen et al 1992a;Cai et al 1996;Canto et al 1997). Similarly, the Gly85 ?…”

Section: Discussionmentioning

confidence: 95%

Novel compound heterozygous mutations in the SRD5A2 gene from 46,XY infants with ambiguous external genitalia

Vilchis

Valdez²,

Ramos

et al. 2008

J Hum Genet

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Dihydrotestosterone is crucial for normal development of external genitalia and prostate in the male embryo. Autosomal recessive mutations in the 5a-reductase type 2 (SRD5A2) gene disrupt the synthesis of dihydrotestosterone in the urogenital tract and give rise to genetic males with undervirilized external genitalia that may be femalelike or ambiguous. In this study, three unrelated 46,XY children (0.5, 3, and 8 years old) who presented severe undermasculinization at birth were examined for genetic abnormalities in the SRD5A2 gene. Coding sequence abnormalities were ascertained by exon-specific polymerase chain reaction (PCR), single-stranded conformational polymorphism (SSCP), and sequencing analysis. Functional properties of the mutant alleles were investigated by means of site-directed mutagenesis assays. DNA molecular studies showed that all three patients were compound heterozygotes for SRD5A2 mutations. Patient 1 had a point mutation 547G ? A in exon 3 (G183S) and a novel dinucleotidic mutation 634,635CC ? TG in exon 4 (P212X). This double change results in premature termination signal (TGA) at codon 212, which predicts the expression of a truncated 211-amino acid protein. Patient 2 was the carrier of mutations G115D in exon 3 and S210F in exon 4. Patient 3 had two substitution mutations in exon 1, including a novel G ? C transversion at nucleotide 169 (E57Q) and a G ? A transition at nucleotide 254 (G85D). In transitory transfection assays, the recombinant cDNAs harboring mutations E57Q and G85D showed residual 5a-reductase activity, whereas those with mutations G115D, S210F, and P212X were devoided of activity. In contrast, the G183S substitution affected the catalytic activity of the enzyme by decreasing its affinity for testosterone substrate. We describe six different mutations of the SRD5A2 gene detected in three children with genital ambiguity. These genotypes are consistent with the clinical phenotype of steroid 5a-reductase 2 deficiency. Our data suggest that the combined gene variants (E57Q/G85D, G115D/S210F, and G183S/P212X) result in subfunctional or nonfunctional enzymes, causing masculinization defects in these patients. This further underscores that exon 4 of SRD5A2 may be a site prone to inactivating mutations.

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“…Their father was healthy and was the carrier of L224H. Canto et al 16 reported a patient with penoscrotal hypospadias, who carried G203S and G115D, and studies indicated that the activity of SRD5A2 and the synthesis of DHT decreased in cultured genital skin fibroblasts carrying these mutations. In this study, some heterozygous mutations in SRD5A2 were also found in five patients, healthy parents (Table 3) and controls.…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of five candidate genes in Chinese patients with hypospadias

et al. 2004

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Hypospadias is the displacement of the urethral meatus from the tip of the glans to the ventral side of the phallus. During fetal development, SRY, SOX9, WT1, SRD5A2 and AR are important at different stages in the differentiation and development of the male genital system. Mutations in these genes impair masculinization and may be associated with hypospadias. In order to explore these possibilities, we employed polymerase chain reaction and direct sequencing to analyze the coding regions of these five genes in 90 Chinese hypospadias patients. We found a total of 16 different mutations in SRD5A2, AR and WT1 in 24 of these 90 patients. Seven mutations are novel. No mutation was found in SRY or SOX9. SNP V89L found in SRD5A2 was statistically significant between patients and controls. Our results indicated that mutations in SRD5A2, AR and WT1 were associated with hypospadias. In conclusion, mutations are frequently found in genes that control androgen action and metabolism, but are seldom found in genes active in the early phase of sex determination and differentiation. Mutations in AR, SRD5A2 or WT1 seem to be associated not only with hypospadias but also with micropenis.

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Mutations of the 5α‐reductase Type 2 gene in eight Mexican patients from six different pedigrees with 5α‐reductase‐2 deficiency

Cited by 78 publications

References 15 publications

Clinical Characterization and Analysis of the <i>SRD5A2 </i>Gene in Six Korean Patients with 5α-Reductase Type 2 Deficiency

Clinical Characterization and Analysis of the <i>SRD5A2 </i>Gene in Six Korean Patients with 5α-Reductase Type 2 Deficiency

Novel compound heterozygous mutations in the SRD5A2 gene from 46,XY infants with ambiguous external genitalia

Mutation analysis of five candidate genes in Chinese patients with hypospadias

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