Study finds association between DGKK gene and hypospadias

Hypospadias is a common congenital malformation of the male external genitalia, affecting 1 in 375 boys. In hypospadias patients, the urethral opening is not located at the tip of the penis, but somewhere halfway, at the base of the penis, or even in the scrotum. Geneticists, epidemiologists and paediatric urologists of the Radboud University Nijmegen Medical Centre in the Netherlands investigated the causes of this congenital malformation. They unexpectedly found a strong association with a gene that was not yet known to be associated with hypospadias (Nature Genetics, nov 28, 2010, on line).

Familial disorder?

Hypospadias patients typically undergo surgery in their first year of life. Still, the malformation may have psychological and sexual consequences that are not willingly discussed. That genetic factors are involved in hypospadias, is demonstrated by the fact that five percent of patients have an affected relative, for example a nephew or an uncle. The inheritance of hypospadias is complex. In most patients multiple small genetic defects are involved. In previous studies, indications were found for a defect in the production of sex hormones that influence the formation of the genitalia. Non-heritable factors must also be involved, however, as the malformation currently seems to occur more frequently than before. "If that is true, we wonder what the cause would be," says one of the leaders of the research project, reproductive epidemiologist Dr. Nel Roeleveld. "Exposure to hazardous compounds or drugs? The maternal dietary pattern? Or a combination of genetic and environmental factors?"

 AGORA

At the Radboud University Nijmegen Medical Centre, the above-mentioned researchers started an extensive project to identify the causes of several congenital disorders, the AGORA project. Hypospadias is one of these disorders. Parents of eight hundred boys who underwent surgery filled out questionnaires about their lifestyle and occupational exposures. These parents and their sons also gave blood. The researchers first looked for changes in a number of genes that play a role in the production of sex hormones. "But we did not find an increased risk," says researcher Loes van der Zanden. "Perhaps, these small genetic changes in sex hormones are less important in the aetiology of hypospadias than was assumed until now."

 X-chromosome

Subsequently, the researchers looked at the complete genome, in a genome-wide association study. This showed an unexpected and remarkably strong association between a few changes in the DGKK gene and hypospadias. A boy with such a modified DGKK gene has a 2.5 times increased risk of hypospadias compared to other boys. To verify this result, the study was repeated with patients from the Karolinska hospital in Stockholm, and the findings were confirmed. The DGKK gene is located at the X-chromosome and is thus in boys inherited from the mother. The only thing that is known about this gene is that it is involved in the communication between cells. How that causes hypospadias is still a mystery.

If a family has a son with hypospadias, the chance that a second son is born with this disorder is 14%. However, if the second son inherited the modified DGKK gene, his chances of developing hypospadias are significantly increased to 27%.

Further studies on combinations of genes and environmental factors involved in the aetiology of hypospadias are not yet finished.