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Submitted on March 3, 2005
Accepted on September 9, 2005
Department of Molecular Medicine, Karolinska institutet, CMM 02, Karolinska University Hospital, SE-17176 Stockholm, Sweden (TH, MK, KL, LF, IK, AN); Department of Women and Child Health, Division of Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, SE-17176 Stockholm, Sweden (AN), E-mail: Agneta.Nordenskjold@cmm.ki.se, Tel: + 46 8 517 76408, Fax: +46 8 517 73620
* To whom correspondence should be addressed. E-mail: Agneta.Nordenskjold{at}cmm.ki.se.
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 cause isolated hypospadias, but the androgenic influence is important during male genital development.
Objective: A key enzyme for the androgenic function is steroid 5 
-reductase (SRD5A2). The V89L polymorphism in the SRD5A2 gene have 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 (OR 0.24, 95% CI 0.14-0.41 for homozygous individuals). This indicates that a fully functional 5--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 AR, SRD5A2 and 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 like hypospadias when several genes as well as environmental factors contribute to the etiology.
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