Molecular Analysis of the <i>SRD5A2</i> in 46,XY Subjects With Incomplete Virilization: The P212R Substitution of the Steroid 5α‐Reductase 2 May Constitute an Ancestral Founder Mutation in Mexican Patients

Vilchis, Felipe; Ramos, Luis; Méndez, Juan Pablo; Benavides, Socorro; Canto, Patricia; Chávez, Bertha

doi:10.2164/jandrol.109.009407

Cited by 35 publications

(34 citation statements)

References 31 publications

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“…The p.G203S mutation on one allele found in all 3 patients was previously reported in patients from Mexico [15,16], Thailand [17] and Korea [18]. The same mutation was also reported previously in 8 Chinese hypospadia patients [19].…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

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

et al. 2011

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“…Regarding molecular diagnosis, 141 patients (94.6%) had 2 mutations detected in SRD5A2 to confirm the diagnosis. Six patients had only 1 mutation detected (2,11,13 ), and 2 patients had no mutation detected in the SRD5A2 gene (11 ).…”

Section: Resultsmentioning

confidence: 97%

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

Chan¹,

But²,

Lee³

et al. 2013

Clinical Chemistry

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BACKGROUND 5α-Reductase 2 deficiency (5ARD) is a known cause of 46,XY disorders of sex development (DSD). Traditionally, the diagnosis relies on dihydrotestosterone (DHT) measurement, but the results are often equivocal, potentially leading to misdiagnosis. We reviewed alternative approaches for diagnosis of 5ARD. METHODS We conducted a retrospective review of the results of urinary steroid profiling (USP) by GC-MS and mutational analysis of SRD5A2 [steroid-5-alpha-reductase, alpha polypeptide 2 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 2)] by PCR and direct DNA sequencing of all 46,XY DSD patients referred to our laboratory with biochemical and/or genetic findings compatible with 5ARD. We also performed a literature review on the laboratory findings of all 5ARD cases reported in the past 10 years. RESULTS Of 16 patients diagnosed with 5ARD between January 2003 and July 2012, 15 underwent USP, and all showed characteristically low 5α- to 5β-reduced steroid metabolite ratios. Four patients had DHT measured, but 2 did not reach the diagnostic cutoff. In all 12 patients who underwent genetic analysis, 2 mutations of the SRD5A2 gene were detected to confirm the diagnosis. Twenty-four publications involving 149 patients with 5ARD were published in the review period. Fewer than half of these patients had DHT tested. Nearly 95% of them had the diagnosis confirmed genetically. CONCLUSIONS 5ARD can be confidently diagnosed by USP at 3 months postnatally and confirmed by mutational analysis of SRD5A2. Interpretation of DHT results may be problematic and is not essential in the diagnosis of 5ARD. We propose new diagnostic algorithms for 46,XY DSD.

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“…The high local incidence of the disorder was explained with the high coefficient of inbreeding in these geographically isolated populations and with a possible founder effect [Vilchis et al, 2010]. Later reports in the literature suggested that some mutations seem to originate in specific geographic regions -e.g., mutation p.Q6X is common for Asian populations, p.L55Q for the Middle East, p.R171S is spread among the Mediterranean region, p.Q126S was reported in patients from West European countries, etc.…”

Section: Discussionmentioning

confidence: 99%

“…The deficiency of 5-alpha-reductase type 2 (5α-reductase-2; OMIM 264600) is an autosomal recessive disorder of the group of 46,XY disorders/differences of sexual development (DSD) [Vilchis et al, 2010]. It is caused by a reduced or absent function of the steroid 5α-reductase-2 enzyme (SRD5A2), which converts testosterone (T) into dihydrotestosterone (DHT) [Imperato-McGinley and Zhu, 2002;Cheon, 2011].…”

mentioning

confidence: 99%

New Territory for an Old Disease: 5-Alpha-Reductase Type 2 Deficiency in Bulgaria

Andonova

Robeva²,

Vazharova³

et al. 2017

Sex Dev

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Disorders/differences of sexual development (DSD) are a group of conditions, some of which can be clinically indistinguishable mainly due to their phenotypic variability. Defining the molecular basis of their wide spectrum is still in progress. The diagnosis of 5-alpha-reductase type 2 (5α-reductase-2) deficiency is difficult especially in newborns and pre-pubertal individuals, and as a result its frequency might be underestimated. In the present study, we describe the clinical characteristics and molecular defects in 3 nonrelated 5α-reductase-2 deficiency patients of Bulgarian descent. Sequencing analysis revealed the mutations p.Y188CfsX9 and p.G196S, and MLPA analysis showed a deletion of exon 1 in the SRD5A2 gene. The observed genetic substitutions were not detected in 76 additionally screened unrelated controls, but a heterozygous healthy carrier of the p.R171S mutation was found. This is the first study on the molecular basis of 5α-reductase-2 deficiency in Bulgaria. It suggests that the carrier frequency of mutations in the SRD5A2 gene might be noteworthy worldwide. There is no correlation between cultural aspects, location, and/or population size and the number of different mutations in SRD5A2 detected, and more efforts should be made to determine the prevalence of this condition in different geographic areas. Our study supports the importance of genetic testing in 46,XY DSD patients, especially in countries or regions where 5α-reductase-2 deficiency has not been reported so far.

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Molecular Analysis of the SRD5A2 in 46,XY Subjects With Incomplete Virilization: The P212R Substitution of the Steroid 5α‐Reductase 2 May Constitute an Ancestral Founder Mutation in Mexican Patients

Cited by 35 publications

References 31 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

Diagnosis of 5α-Reductase 2 Deficiency: Is Measurement of Dihydrotestosterone Essential?

New Territory for an Old Disease: 5-Alpha-Reductase Type 2 Deficiency in Bulgaria

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