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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0446
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6695-6698
Copyright © 2005 by The Endocrine Society

The Valine Allele of the V89L Polymorphism in the 5-{alpha}-Reductase Gene Confers a Reduced Risk for Hypospadias

Hanh T. T. Thai, Mina Kalbasi, Kristina Lagerstedt, Louise Frisén, Ingrid Kockum and Agneta Nordenskjöld

Department of Molecular Medicine (H.T.T.T., M.K., K.L., L.F., I.K., A.N.), Karolinska Institutet, and Department of Women and Child Health (A.N.), Division of Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, SE-17176 Stockholm, Sweden

Address all correspondence and requests for reprints to: Agneta Nordenskjöld, Department of Molecular Medicine, Karolinska Institutet, CMM 02, Karolinska University Hospital, SE-17176 Stockholm, Sweden. E-mail: Agneta.Nordenskjold{at}cmm.ki.se.


   Abstract
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 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Hypospadias is one of the most common malformations in man, with an incidence of 1:300 in newborn boys. No gene has been identified that causes isolated hypospadias, but the androgenic influence is important during male genital development.

Objective: A key enzyme for the androgenic function is steroid 5-{alpha}-reductase (SRD5A2). The V89L polymorphism in the SRD5A2 gene has been studied and found to be of functional importance. The leucine version of the enzyme is 30% less efficient than the valine variant.

Design, Setting, Patients, and Results: We have genotyped 158 hypospadias cases and 96 unaffected controls for this polymorphism and found a significant negative association for the V89 allele in hypospadias (odds ratio, 0.24; 95% confidence interval, 0.14–0.41 for homozygous individuals). This indicates that a fully functional 5-{alpha}-reductase enzyme (homozygous for V89) protects the male urethral development. This association is shown regardless of heredity, ethnicity, and severity of phenotype. We have also sequenced a selected material of 37 sporadic cases of more severe hypospadias for mutations in the androgen receptor AR, SRD5A2, and 17ß-hydroxysteroid dehydrogenase HSD17B3 genes and found only two previously described mutations, one in the AR and one in the SRD5A2 gene.

Conclusion: This finding is in accordance with the assumption that functional polymorphisms may play an important role in complex disorders such as hypospadias when several genes as well as environmental factors contribute to the etiology.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
NORMAL MALE SEX differentiation relies on the effect of androgen. The normal male human urethra develops during fetal wk 8–16, and a premature arrest causes hypospadias. Although hypospadias is one of the most prevalent urogenital malformations, the etiology is still not clearly understood (1). No gene has so far been identified as a common cause of isolated hypospadias. This malformation is regarded as a complex disorder caused by both genetic and environmental influences, either alone or in a combination. In complex disorders, the disease-associated genetic alterations appear to be common polymorphisms affecting gene function rather than mutations, with a more profound effect as commonly found in single gene traits.

Extensive mutation screening in hypospadias has revealed disease-associated sequence alterations predominantly in two genes, the androgen receptor (AR) and the steroid 5-{alpha}-reductase (SRD5A2) genes. However, these mutations are usually found in severe cases of hypospadias often associated with other genital malformations and not the more common and less severe variants of glandular or penile forms (2, 3, 4, 5, 6). In one study, seven mutations in SRD5A2 gene were detected in 81 isolated hypospadias boys with different severity of phenotype (7). Among those, there were five cases with the uncommon polymorphism A49T in homozygous or heterozygous form. In addition, biochemical studies of boys with severe hypospadias have shown a high incidence of enzyme deficiencies in the testosterone metabolic pathway (8). Male pseudohermaphroditism can also be caused by deficiency of 17ß-hydroxysteroid dehydrogenase (HSD17B3) that metabolizes the last step in testosterone production (9). In our group, we have recently performed a genome-wide screen for hypospadias genes by performing a sibling pair analysis of 69 families (10). One of the regions of interest for hypospadias genes turned out to include the region in which the HSD17B3 gene is located (9q22). This led us to investigate the role of HSD17B3 as a candidate gene for isolated hypospadias.

We decided to perform sequencing of the AR, SRD5A2, and HSD17B3 genes in hypospadias cases to elucidate the role of these genes in the pathogenesis of the malformation.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We included 158 boys that have been operated for hypospadias in this study. Peripheral blood or penile skin tissue was obtained at surgery, and constitutional DNA was extracted according to routine protocols with phenol chloroform extraction. Initially, we sequenced the AR and SRD5A2 genes in a subset of 37 boys with either a more severe phenotype or a familial form of hypospadias. The HSD17B3 gene was sequenced in 19 boys with hypospadias from the families that contributed most to the linkage peak in the vicinity of the HSD17B3 gene (10).

In all cases, we gathered information on whether the malformation was sporadic or familial. Data were also obtained in 153 cases concerning ethnicity and in 123 cases concerning phenotype. Phenotypes were graded into mild (glandular, coronar, and distal penile forms), medium severity (penile with chordee), or severe form (penoscrotal, scrotal, or perineal hypospadias). All samples were obtained after informed consent from the parents. We also included DNA from 96 control persons of Caucasian origin. The local Ethics Committee of Karolinska Institutet has approved this study.

DNA sequencing was performed from PCR products amplified by exon-flanking primers (exon 2–8 in AR gene, exon 1–5 in SRD5A2 gene, and exon 1–11 in the HSD17B3 gene). A list of primers is available on request. PCRs were performed in a final volume of 25 µl containing 1x PCR buffer II (Applied Biosystems, Foster City, CA), 100 µM dNTP (Invitrogen, Gaithersburg, MD), 2.5 mM MgCl2 (Applied Biosystems), 1.25 U AmpliTaq Gold (Applied Biosystems), 10 pmol of each primer, and approximately 100 ng of genomic DNA. Amplification conditions were 95 C for 15 min, followed by 30 cycles of 96 C for 30 sec, 56 C for 30 sec, 72 C for 45 sec, and final step at 72 C for 2 min. Amplifications were performed in a PTC-225 (MJ Research, Watertown, MA). DNA sequence reactions were performed using Big Dye Primer sequencing Ready reaction –21M13 kit (Applied Biosystems). The sequencing reactions were performed according to the recommendation of the manufacturer and analyzed on an ABI 310 DNA sequencer (Applied Biosystems).

The SRD5A2 gene was analyzed for the V89L polymorphism using allele-specific PCR. The forward primer (5'-ACACGGAGAGCCTGAAGC-3'), the nonspecific reverse primer (5'-TCGGTGCGCGCTCCACG-3'), and either the valine-specific reverse primer (5'-AACGCTACCTGTGGAAGTAATGTA-3') or the leucine-specific reverse primer (5'-ACGCTACCTGTGGAAGTAATGTAG-3') was used. Amplifications were performed in an Applied Biosystems GeneAmp PCR system 9700 as follows: initial denaturation at 95 C for 2 min; 15 cycles of 94 C for 1 min, 63 C for 1 min, and 72 C for 2 min; 25 cycles of 94 C for 1 min, 59 C for 1 min, and 72 C for 2 min; and the final extension at 72 C for 5 min. PCR products were resolved on a 3% agarose gel, stained with ethidium bromide, visualized under UV light, and photographed.

Odds ratios (ORs) were calculated using Woolf’s method as cross products of 2 x 2 contingency tables (11). Miettinen’s test-based method was used for estimating 95% confidence intervals (95% CI) to demonstrate the precision of the OR estimate (12). The level of statistical significance was estimated by {chi}2 analysis with Yate’s correction. P values were corrected for multiple comparisons by multiplying them with the number of comparisons made (n = 27). The number of independent comparisons made was calculated as number of phenotypes/ethnic groups analyzed multiplied by three.


   Results
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 Abstract
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 Patients and Methods
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Discussion
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Exons 2–5 and 7–8 of the AR gene were normal in 37 cases. In one boy with scrotal hypospadias, we detected a point mutation in exon 6 in codon 798, CAA (glutamine) was changed to GAA (glutamic acid) (Fig. 1AGo).



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  		FIG. 1. A, Mutation in the AR gene. I, A hemizygous Q798E mutation in patient (GAA). II, Control in codon 798 with the codon CAA. B, Mutation in the SRD5A2 gene. I, A heterozygous G196S mutation in case number 26 (GGT/AGT). II, The same heterozygous mutation in the mother. III, Normal sequence in the father (GGT).

 
No mutations were found in the coding regions of HSD17B3 in the subgroup of boys with familial hypospadias chosen from the sibling pair analysis (19 cases). In two cases, a previously described heterozygous polymorphism for G874S was found.

DNA sequencing of the SRD5A2 exon 1–5 in 37 cases revealed only one mutation in heterozygous form, GGT (glycine) to AGT (serine) in codon 196. This boy was born with scrotal hypospadias and chordee. The mutation was inherited from the mother, whereas the father had a normal sequence (Fig. 1BGo). No mutation was detected in the other exons. One boy with isolated midpenile hypospadias was heterozygous for the A49T polymorphism. All of the other cases had the more common A49 allele in homozygous form.

DNA sequencing of the SRD5A2 gene in the initial 37 hypospadias boys revealed that the rare allele (leucine) of the V89L polymorphism in exon 1 was overrepresented in this material compared with previously published results (13). In 37 cases, we detected 23 boys being homozygous for the leucine allele, 11 were heterozygous, and only three cases were homozygous for the more common valine allele. This corresponds to an allele frequency of 0.23 for the valine allele and 0.77 for the leucine allele.

We therefore analyzed an additional 121 hypospadias cases and controls and performed an allele-specific PCR for the V89L polymorphism. We also confirmed the sequencing data by genotyping the 37 cases for which we had performed the sequencing analysis. Overall, in the 158 hypospadiac cases, the allele frequencies were 48% for valine (V89) and 52% for leucine (L89) compared with controls, 71 and 29%, respectively (Tables 1Go and 2Go). Boys homozygous for valine (V89/V89) had an OR for having hypospadias of 0.24 (95% CI, 0.14–0.41), Pc value = 7 x 10–6 (in which Pc indicates P value corrected for the number of comparisons made). In contrast, carriers of the leucine allele (L89) in homozygous or heterozygous form had an OR of about 2 (1.9 and 2.9, respectively). Allele frequencies did not differ between sporadic and familial cases. The homozygous carriers of valine showed similar evidence of association OR (0.24), Pc value = 1 x 10–3, respectively. This negative association was more pronounced in non-Swedish population (Table 1Go), especially in the Turkish cases, probably due to differences in allele frequencies between the Swedish and Turkish populations. Furthermore, the protective effect of being homozygous for the valine allele was more significant in mild phenotypes, although it was also evident in severe hypospadias.


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  		TABLE 1. Association of the valine allele of the V89L polymorphism in the SRD5A2 gene with hypospadias

 

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  		TABLE 2. Association of V89L polymorphism with hypospadias

 

   Discussion
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 Abstract
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 Patients and Methods
 Results
 Discussion
References
 
The mutation in SRD5A2 detected in this study (G196S) has been described previously in association with hypospadias. The mutation G196S in homozygous form was found in two patients with severe hypospadias, micropenis, and bifid scrotum, as well as in three other sibling pairs with scrotal hypospadias, microphallus, and cryptorchidism (14, 15). The correlation between phenotype and the impairment of enzyme function has been explained by the biochemical mechanism. Nicotinamide adenine dinucleotide phosphate (NADPH) is the cofactor for the enzyme activity of SRD5A2. Eight different amino acids, including glycine 196, contribute to the NADPH cofactor-binding site in the carboxy terminal half (16). Mutations in this site decrease the half-life of the enzyme and reduce the affinity of NADPH, and the activity is about 10% of the normal enzyme. Moreover, the enzyme becomes unstable and exhibits a rapid turnover. However, the G196S mutation does not disrupt the NADPH binding completely, thus leading to a less severe phenotype. In most published reports, this mutation has lead to hypospadias and a male upbringing.

The Q798E mutation in the AR gene has been described in some cases with different external genitalia. These subjects have had a variety of genital phenotypes ranging from clitoromegaly and labial fusion to hypospadias in association with cryptorchidism and micropenis to normal male with azoospermia (17, 18). To our knowledge, the boy in this study with penoscrotal hypospadias is the first case of Q798E mutation with isolated hypospadias. The association of this mutation with various genital defects suggests that it has a vague role. Despite being located in a functional subdomain within the ligand-binding domain of AR gene, Q798E affects the transactivation function of AR rather than binding. Because of a deceptive but significant role in the trans-activation role of AR, Q798E mutation is consistent with various external genital abnormalities, including hypospadias.

Our sequence data together with previous studies performed by our group (6) confirm that mutations in coding regions in the AR, SRD5A2, and HSD17B3 genes are unusual in isolated or familial hypospadias, especially in Swedish cases.

The findings on the V89L polymorphism in the SRD5A2 gene were more interesting. This polymorphism has been extensively studied in prostate cancer in different populations and with somewhat conflicting results concerning association (13, 19). Leucine in codon 89 (L89) has been shown to result in almost 30% reduced enzyme activity and thus lower concentration of testosterone metabolites (20, 21, 22, 23). The possibility of different function of these two gene products makes this polymorphism especially interesting in the pathogenesis of hypospadias.

The frequency of valine and leucine alleles in Caucasian control populations is about 0.7 and 0.3, respectively. A higher leucine frequency has been reported in Asian populations (0.43) and the lowest in African-Americans (0.24) (24). The allele frequency in our control material is in accordance with previous observations in Caucasian populations with an allele frequency of 0.71 for valine and 0.29 for leucine, respectively. In the total hypospadias material, the frequency of the leucine allele is overrepresented (0.48 for valine and 0.52 for leucine). We found no difference in allele frequencies between familial and sporadic cases.

The Turkish patients have an even higher leucine frequency than the Swedish patients. Because the selection of controls was not population based, the magnitude of the OR should be interpreted with caution. That is, the reported OR should not be interpreted as the risk for hypospadias confirmed by a particular genotype. This is especially the case for the OR for the Turkish patients in which the controls used in the comparison came from Sweden. However, the identified association should give an indication that the V89L polymorphism is a susceptibility factor for hypospadias. This may reflect the ethnicity, but we were not able to analyze that due to lack of controls from this population.

We have phenotypic data on 123 of the cases (78%). In the group with severe hypospadias (penoscrotal, scrotal, and perineal), 26% are homozygous for valine compared with our control material with 61.5% (Table 2Go). We hypothesize that optimal function of both alleles of the SRD5A2 enzyme protects against disturbances of a genetic or environmental factor and therefore reduces the risk for hypospadias. Conversely, a slightly less well-functioning enzyme enables other mechanisms to intervene with the urethral development. One such factor could be birth weight, indicating a diminished growth capacity or a relative lack of hormones. There are studies indicating that the leucine allele (L89) has a lower enzymatic activity (20, 21, 22, 23). This supports the notion that the V89L polymorphism is a susceptibility factor for hypospadias in itself or is in linkage equilibrium with another susceptibility factor. The same finding was also reported recently in a Chinese population with a higher incidence of the leucine allele among hypospadias cases than in controls (25).

The A49T variant found previously in five hypospadias cases was only detected in one case in our series of 37 cases (7). This infrequent polymorphism has been reported to cause an increased enzyme function (21).

In summary, the V89 allele of the SRD5A2 gene in homozygous form reduces the risk for hypospadias.


   Acknowledgments
 
We are grateful to Ulla Grandell and Margareta Tapper-Persson for excellent laboratory assistance and to Mir Davood Omrani for support.


   Footnotes
 
This study was supported by grants from the Swedish Research Council, HRH Crown Princess Lovisa Foundation, Frimurarna, Magnus Bergvall Foundation, Marcus Borgström Foundation, and Karolinska Institutet.

First Published Online September 20, 2005

Abbreviations: AR, Androgen receptor gene; CI, confidence interval; HSD17B3, 17ß-hydroxysteroid dehydrogenase gene; NADPH, nicotinamide adenine dinucleotide phosphate; OR, odds ratio; SRD5A2, steroid 5-{alpha}-reductase gene.

Received March 3, 2005.

Accepted September 9, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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