Table of Contents  
Year : 2018  |  Volume : 20  |  Issue : 5  |  Page : 518-519

Identification of a novel mutation in the SRD5A2 gene of one patient with 46,XY disorder of sex development

1 The Second Clinical Laboratory, Xingtai People's Hospital, Xingtai 054000, China Nutrition Department, Xingtai People's Hospital, Xingtai 054000, China Department of Paediatrics, Xingtai People's Hospital, Xingtai 054000, China Function Examination Department, Xingtai People's Hospital, Xingtai 054000, China Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China

Date of Submission13-Oct-2017
Date of Acceptance07-Apr-2018
Date of Web Publication25-May-2018

Correspondence Address:
Shu-Jun Li
The Second Clinical Laboratory, Xingtai People's Hospital, Xingtai 054000, China

Xiao-Wei Dou
Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aja.aja_34_18

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How to cite this article:
Li SP, Li LW, Sun MX, Chen XX, Wang XF, Li ZK, Zhou SY, Zhai DC, Geng SX, Li SJ, Dou XW. Identification of a novel mutation in the SRD5A2 gene of one patient with 46,XY disorder of sex development. Asian J Androl 2018;20:518-9

How to cite this URL:
Li SP, Li LW, Sun MX, Chen XX, Wang XF, Li ZK, Zhou SY, Zhai DC, Geng SX, Li SJ, Dou XW. Identification of a novel mutation in the SRD5A2 gene of one patient with 46,XY disorder of sex development. Asian J Androl [serial online] 2018 [cited 2022 Jun 29];20:518-9. Available from:

Shu-Ping Li, Li-Wei Li
These authors contributed equally to this work.

Dear Editor,

46, XY disorder of sex development (DSD) is characterized by a female phenotype in an individual with a normal 46, XY karyotype.[1] The clinical phenotype of 46, XY DSD is characterized by bilateral undescended testes and a normal female appearance, including breasts, female external genitalia, and other secondary sex characteristics, but the absence of a uterus or ovaries.[2] Development of the male external genitalia in the fetal period depends on the biosynthesis of testosterone (T), the conversion of T into dihydrotestosterone (DHT) by steroid 5α-reductase type 2 (SRD5A2), and the response of functionally active androgen receptors in genital tissues.[3] The disruption of any of these stages will block the differentiation of internal and external genitalia and cause 46, XY DSD.

The etiology of 46, XY DSD remains largely unclear. The most common identifiable cause of 46, XY DSD is androgen insensitivity syndrome (AIS). AIS is an X-linked recessive genetic disorder with a normal 46, XY karyotype that is caused by a loss of androgen expression or androgen receptor mutation.[4] The second cause of 46, XY DSD is SRD5A2 deficiency, which is an autosomal recessive disorder caused by decreased or loss of SRD5A2 function.[5] The loss of functional SRD5A2 causes an inability to convert T into DHT, the major hormone responsible for normal male appearance and male sex characteristics.[6] Therefore, mutated SRD5A2 gene products block the biosynthesis of DHT, resulting in 46, XY DSD. Thus far, more than 60 mutations have been reported in the SRD5A2 gene.

The primary objective of this study is to identify the etiology of 46, XY DSD. A 2-year-old female was referred to our hospital. A physical examination was performed, including height, weight, and female external genitalia. A color Doppler ultrasonic diagnostic instrument (Voluson E8, GE, Salzburg, Austria) was used to detect male or female internal genital organs, including testis, uterus, and ovaries. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progestin (PROG), T, and prolactin (PRL) for the proband were measured using UniCel Dxl 800 atutomatic immunoassay system (Beckman Coulter, Brea, CA, USA). Chromosome karyotype analysis was used to analyze the proband's karyotype. The genomic DNA was extracted from the peripheral blood samples of the proband and sequencing was performed by the Beijing Genomics Institute (BGI) using the Illumina Genome Analyzer IIx (Illumina Inc., San Diego, CA, USA) for 219 DSD-related genes, including sex chromosomal abnormality, germinal aplasia, and other DSD-related genes. Informed consent was obtained from the child's parents and all experiments were approved by the Medical Ethical Committee of Xingtai People's Hospital Xingtai, China.

The physical examination of the 2-year-old female revealed normal female external genitalia, but a blind-ending vagina. An ultrasound test demonstrated that the proband did not have a uterus or ovaries, but have testis in the left labium majus and right groin. Cytogenetic analysis showed that the patient had a 46, XY karyotype with no apparent anomalies in the chromosome number or chromosomal structure. The hormone test showed that FSH (0.54 mIU ml−1), LH (0.12 mIU ml−1), and T (<0.1 ng ml−1) levels of the proband were lower compared to normal males.

A total of 219 DSD-related genes were sequenced by BGI using the Illumina Genome Analyzer IIx. Sequence analysis showed that the sequences of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) and androgen receptor (AR) were normal, which synthesize testosterone and respond to DHT, respectively. However, we identified two heterozygous mutations in the SRD5A2 gene of the proband. The mutation 695A>G changes amino acid 232 from histidine to arginine (p.H232R). This mutation has not been previously reported in the databases of the normal human genome, including the dbSNP, ESP6500, 1000 Genomes, and BGI sequencing databases. The second SRD5A2 gene mutation was 16C>T, which introduced a stop codon (p.Q6X). This mutation was previously reported and related to the pathogenesis of 46, XY DSD[7] [Figure 1].
Figure 1: Sequencing analysis of the SRD5A2 mutation of the proband. (a) The 695A>G mutation changes amino acid 232 from histidine to arginine (p.H232R). (b) The 16C>T mutation found in the SRD5A2 gene introduced a stop codon. SRD5A2: steroid 5a-reductase type 2.

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To date, over 60 mutations in the SRD5A2 gene have been reported in patients with 46, XY DSD.[8] In this case report, we identified the compound heterozygous mutation (p.H232R/p.Q6X) in a Chinese patient with 46, XY DSD. The compound heterozygosity has two different recessive alleles at a particular locus that can cause genetic disease in a heterozygous state. This paper is the first report to identify the p.H232R mutation in a subject with 46, XY DSD. In a previous report, p.H230P and p.H231R mutations in exon 4 of the SRD5A2 gene were found to cause 46, XY DSD. Histidine 232 of SRD5A2is located in a stretch of three histidines (residues 230–232). Mutations in two of these histidines (residues 230 and 231) inactivate or impair SRD5A2function.[9] Therefore, we speculate that the p.H232R mutation in SRD5A2, like the mutations at amino acids 230 and 231, affects the domain function and thus inactivates SRD5A2enzyme activity. The second SRD5A2 gene mutation (p.Q6X) results in a stop codon. The mutation produces a truncated protein, which has lost its ability to bind the testosterone receptor. The compound heterozygous p.G203S/p.Q6X mutations were identified in patients with hypospadias and 46, XY DSD.[7] In most cases of SRD5A2 mutation, the testes located in the inguinal region that implied DHT may play a critical role in testis descent.[1] We also found that the patients with the compound heterozygous mutation p.H232R/p.Q6X is related to the abnormality of testis descent. Based on our results, the compound heterozygous mutation p.H232R/p.Q6X in SRD5A2should be regarded as a causative mutation of 46, XY DSD.

In conclusion, our molecular diagnosis of a patient with 46, XY DSD identified a previously unknown mutation (p.H232R) and the previously reported mutation (p.Q6X) in the SRD5A2 gene. To our knowledge, this is the first report that a patient with SRD5A2 deficiency carries the p.H232R SRD5A2 mutant. Our findings expand the mutation spectrum associated with the 46, XY DSD and may contribute to the elucidation of the molecular mechanisms of the H232R mutant in SRD5A2functional defects.

  Author Contributions Top

SPL, LWL, XXC, XFW, ZKL, SYZ, DCZ, and SXG carried out the molecular genetic studies. SPL, LWL, and MXS carried out the immunoassays. XWD participated in the sequence alignment. SPL, LWL, SJL, and XWD participated in the design of the study and drafted the manuscript. All authors read and approved the final manuscript.

  Competing Interests Top

All authors declared no competing interests.

  References Top

Mendonca BB, Batista RL, Domenice S, Costa EM, Arnhold IJ, et al. Steroid 5α-reductase 2 deficiency. J Steroid Biochem Mol Biol 2016; 163: 206–11.  Back to cited text no. 1
Gomez-Lobo V, Amies Oelschlager A. Disorders of sexual development in adult women. Obstet Gynecol 2016; 128: 1162–73.  Back to cited text no. 2
Blaschko SD, Cunha GR, Baskin LS. Molecular mechanisms of external genitalia development. Differentiation 2012; 84: 261–8.  Back to cited text no. 3
Mendoza N, Motos MA. Androgen insensitivity syndrome. Gynecol Endocrinol 2013; 29: 1–5.  Back to cited text no. 4
Andonova S, Robeva R, Vazharova R, Ledig S, Grozdanova L, et al. New territory for an old disease: 5-alpha-reductase type 2 deficiency in Bulgaria. Sex Dev 2017; 11: 21–8.  Back to cited text no. 5
Shabir I, Khurana M, Joseph A, Eunice M, Mehta M, et al. Phenotype, genotype and gender identity in a large cohort of patients from India with 5α-reductase 2 deficiency. Andrology 2015; 3: 1132–9.  Back to cited text no. 6
Zhang M, Yang J, Zhang H, Ning G, Li X, et al. Anovel SRD5A2 mutation with loss of function identified in Chinese patients with hypospadias. Horm Res Paediatr 2011; 76: 44–9.  Back to cited text no. 7
Kang HJ, Imperato-McGinley J, Zhu YS, Rosenwaks Z. The effect of 5α-reductase-2 deficiency on human fertility. Fertil Steril 2014; 101: 310–6.  Back to cited text no. 8
Wigley WC, Prihoda JS, Mowszowicz I, Mendonca BB, New MI, et al. Natural mutagenesis study of the human steroid 5a-reductase 2 isozyme. Biochemistry 1994; 33: 1265–70.  Back to cited text no. 9


  [Figure 1]

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