A Potential Pathogenic SRD5A2 Mutation and rs632148, rs523349 and rs522638 Polymorphisms in Increasing the Risk of Syndromic Hypospadias in Indonesian Population

Rizki Diposarosa, Yunisa Pamela, Herry Herman, Yunia Sribudiani


BACKGROUND: Hypospadias, a congenital birth defect in male, is the opening of the urethra located on the ventral side of the penis. Several mutations in SRD5A2 encoding steroid 5 alpha-reductase type 2 protein have been identified in hypospadias and polymorphisms in this gene have been known to be associated with an increased risk of hypospadias. In this study, several crucial molecular analyses of the SRD5A2 gene and the association of the identified variants to the risk of syndromic hypospadias in Indonesian population were conducted.

METHODS: Thirty-two isolated and 29 syndromic hypospadias patients were enrolled in this study. DNA was isolated from whole blood for the amplification of all exons and exon-intron boundaries of SRD5A2 by polymerase chain reaction (PCR), followed by Sanger sequencing. In silico analysis was performed using PolyPhen-2, Sorting Intolerant from Tolerant (SIFT) and Align GVGD. Statistical analysis was performed using Chi-squared test.

RESULTS: A novel missense mutation c.32T>C/p.Leu11Pro was identified in one isolated hypospadias patient and the in silico analysis predicted the mutation to be pathogenic. Three polymorphisms were identified, two in the non-coding region (c.-62G>C/rs632148 and c.281+15T>C/rs522638) and one in exon-1 (c.265C>G/p.Val89Leu/rs523349). Mutant alleles of these polymorphisms were significantly associated with syndromic hypospadias with odds ratios (OR) of 3.4, 3.13 and 2.54 respectively.

CONCLUSION: This study suggests that SRD5A2 mutation is one of the causes of hypospadias in Indonesian population and rs632148, rs523349 and rs522638 polymorphisms are significantly associated with an increased risk of syndromic hypospadias.

KEYWORDS: mutation, polymorphism, SRD5A2, syndromic hypospadias

Full Text:



Springer A, van den Heijkant M, Baumann S. Worldwide prevalence of hypospadias. J Pediatr Urol. 2016; 12(3): 152.e1-7, CrossRef.

Stoll C, Alembik Y, Roth MP, Dott B. Genetic and environmental factors in hypospadias. J Med Genet. 2008; 27(9): 559-63, CrossRef.

Blaschko SD, Cunha GR, Baskin LS. Molecular mechanisms of external genitalia development. Differentiation. 2012; 84(3): 261-8, CrossRef.

van der Horst HJ, de Wall LL. Hypospadias, all there is to know. Eur J Pediatr. 2017; 176(4): 435-41, CrossRef.

Bouty A, Ayers KL, Pask A, Heloury Y, Sinclair AH. The genetic and environmental factors underlying hypospadias. Sex Dev. 2015; 9(5): 239-59, CrossRef.

Joodi M, Amerizadeh F, Hassanian SM, Erfani M, Ghayour-Mobarhan M, Ferns GA, et al. The genetic factors contributing to hypospadias and their clinical utility in its diagnosis. J Cell Physiol. 2018; 233(4): 2882-8, CrossRef.

Hasegawa Y, Kon M, Nagasaki K, Matsubara Y, Muroya K, Nakabayashi K, et al. Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients. Hum Reprod. 2015; 30(3): 499-506, CrossRef.

Kalfa N, Gaspari L, Ollivier M, Philibert P, Bergougnoux A, Paris F, et al. Molecular genetics of hypospadias and cryptorchidism recent developments. Clin Genet. 2019; 95(1): 122-31, CrossRef.

Kojima Y, Kohri K, Hayashi Y. Genetic pathway of external genitalia formation and molecular etiology of hypospadias. J Pediatr Urol. 2010; 6(4): 346-54, CrossRef.

Snodgrass W, Macedo A, Hoebeke P, Mouriquand PDE. Hypospadias dilemmas: A round table. J Pediatr Urol. 2011; 7(2): 145-57, CrossRef.

Rouzrokh M, Ghanbari M, Mirfakhraie R, Rahimi M, Fazeli Z, Omrani MD, et al. Association of SRD5A2 gene mutations with risk of hypospadias in the Iranian population. J Endocrinol Invest. 2016; 40(4): 391-6, CrossRef.

Kalfa N, Philibert P, Werner R, Audran F, Bashamboo A, Lehors H, et al. Minor hypospadias: The "tip of the iceberg" of the partial androgen insensitivity syndrome. PLoS One. 2013; 8(4): e61824, CrossRef.

Kim K, Liu W, Cunha GR, Russell DW, Huang H, Shapiro E, et al. Expression of the androgen receptor and 5α-reductase type 2 in the developing human fetal penis and urethra. Cell Tissue Res. 2002; 307(2): 145-53, CrossRef.

Shabir I, Khurana ML, Joseph AA, Eunice M, Mehta M, Ammini AC. Phenotype, genotype and gender identity in a large cohort of patients from India with 5α-reductase 2 deficiency. Andrology. 2015; 3(6): 1132-9, CrossRef.

Thai HTT, Kalbasi M, Lagerstedt K, Frisén L, Kockum I, Nordenskjöld A. The valine allele of the V89L polymorphism in the 5-α-reductase gene confers a reduced risk for hypospadias. J Clin Endocrinol Metab. 2005; 90(12): 6695-8, CrossRef.

Fu XH, Zhang WQ, Qu XS. Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children. Genet Mol Res. 2016; 15(1): 15018232, CrossRef.

Yuan S, Meng L, Zhang Y, Tu C, Du J, Li W, et al. Genotype-phenotype correlation and identification of two novel SRD5A2 mutations in 33 Chinese patients with hypospadias. Steroids. 2017; 125: 61-6, CrossRef.

Zhang K, Li Y, Mao Y, Ma M. Steroid 5-alpha-reductase type 2 (SRD5A2) gene V89L polymorphism and hypospadias risk: A meta-analysis. J Pediatr Urol. 2017; 13(6): 630.e1-9, CrossRef.

Carmichael SL, Witte JS, Ma C, Lammer EJ, Shaw GM. Hypospadias and variants in genes related to sex hormone biosynthesis and metabolism. Andrology. 2014; 2(1): 130-7, CrossRef.

Marzuki NS, Idris FP, Kartapradja HD, Harahap AR, Batubara JRL. Characterising SRD5A2 gene variants in 37 Indonesian patients with 5-alpha-reductase type 2 deficiency. Int J Endocrinol. 2019; 2019: 7676341, CrossRef.

Samtani R, Bajpai M, Vashisht K, Ghosh PK, Saraswathy KN. Hypospadias risk and polymorphism in SRD5A2 and CYP17 genes: Case-control study among Indian children. J Urol. 2011; 185(6): 2334-9, CrossRef.

Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010; 7(4): 248-9, CrossRef.

Ng PC, Henikoff S. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003; 31(13): 3812-4, CrossRef.

Tavtigian SV, Deffenbaugh AM, Yin L, Judkins T, Scholl T, Samollow PB, et al. Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet. 2006; 43(4): 295-305, CrossRef.

Zheng D, Zhao J, Wang F, Zhang L, Xu C, Li C, et al. Clinical and molecular characterization of 5α-reductase type 2 deficiency due to mutations (p.Q6X, p.R246Q) in SRD5A2 gene. Endocr J. 2018; 65(6): 645-55, CrossRef.

Tsai MC, Chou YY, Lin SJ, Tsai LP. A novel SRD5A2 mutation in a Taiwanese newborn with ambiguous genitalia. Kaohsiung J Med Sci. 2012; 28(4): 231-5, CrossRef.

Yang Q, Qu WY, Yang L, Wang K, Tu HY, Wang J. Literature on the aetiology of hypospadias in the last 5 years: Molecular mechanism and environmental factors. Andrologia. 2014; 46(6): 583-91, CrossRef.

Makridakis NM, di Salle E, Reichardt JK V. Biochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II. Pharmacogenetics. 2000; 10(5): 407-13, CrossRef.

Hsing AW, Chen C, Chokkalingam AP, Gao Y tang, Dightman DA, Nguyen HT, et al. Polymorphic markers in the SRD5A2 gene and prostate cancer risk. Cancer Epidemiol Prev Biomarkers. 2001; 10(10): 1077-82, article.

DOI: https://doi.org/10.18585/inabj.v16i3.2968

Copyright (c) 2024 The Prodia Education and Research Institute

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.


Indexed by:






The Prodia Education and Research Institute