A mutation in bilirubin uridine 5'-diphosphate-glucuronosyltransferase isoform 1 causing Crigler-Najjar syndrome type II

BACKGROUND: Inherited unconjugated hyperbilirubinemia in Crigler-Najjar type II (CN II) is caused by a strong reduction of bilirubin uridine 5'-diphosphate-glucuronosyltransferase (B-UGT) activity. Both B-UGT isoenzymes (B-UGT1 and B-UGT2) identified in humans are derived from a single gene by alternative splicing. To clarify the genetic background of CN II and the role of both B-UGT forms in the physiological clearance of bilirubin, we have studied a large kindred with two CN II patients. METHODS: From genomic DNA all B-UGT encoding exons were amplified by polymerase chain reaction and sequenced to identify mutations causing CN II. RESULTS: The CN II patients were found to be homozygous for a nucleotide shift in the unique region of B-UGT1, changing a arginine into a tryptophan, and also for a nucleotide shift in the unique region of B-UGT2, changing a leucine into a valine. Analysis of other family members and of 50 control subjects showed that the mutation in B-UGT1 causes CN II, whereas the mutation in B-UGT2 is a polymorphism. CONCLUSIONS: CN II syndrome appears to be caused by a homozygous mutation in B-UGT1. This indicates that B-UGT1 is the physiological important bilirubin glucuronidating isoform