The risk of contracting a serious form of jaundice is three to five times higher in infants carrying two specific genetic mutations, each of which is generally benign when it occurs alone. This finding, reported in today's Proceedings of the National Academy of Sciences, is an important example of a disease caused by the interaction of two genes.
For more than 3 decades, researchers have known that severe neonatal jaundice is linked to a genetic mutation that cuts production of an enzyme called G-6-PD. The condition, formally called hyperbilirubinemia, can lead to a dangerous brain disorder called kernicterus. But it was a mystery why many infants deficient in G-6-PD never develop jaundice. Researchers got a break in the case 3 years ago, when Gilbert's syndrome--a mild jaundice in adults--was linked to a mutation in another enzyme, UGTP1.
To check out the lead, a group of Israeli medical scientists, and colleagues at the Scripps Research Institute in La Jolla, California, analyzed DNA from 371 newborns in a population of Mediterranean-Jewish descent--a group with a high incidence of hyperbilirubinemia. The researchers found that the 131 G-6-PD-deficient infants had a much higher risk for severe jaundice if they also carried a mutant form of the gene for Gilbert's syndrome. Severe jaundice struck nearly 33% of the G-6-PD-deficient newborns carrying one copy of the mutant UDPGT1 gene, and 50% of the G-6-PD-deficient infants carrying two mutant copies. In contrast, only 7% to 15% of newborns with mutated versions of either gene--or normal copies of both--were afflicted. In these cases, researchers believe, hyperbilirubinemia is caused by some other factor.
The discovery is "a very clean and elegant example" of two genes interacting to cause disease, says Arno Motulsky, a medical geneticist at the University of Washington, Seattle. Many other diseases, such as diabetes and hypertension, often stem from multiple genetic mutations, but researchers have struggled to identify the affected genes.