Patients with
Crigler-Najjar syndrome (CN) type I inherit an autosomal recessive trait for
hyperbilirubinemia, which is characterized by the total absence of
bilirubin UDP-glucuronosyltransferase (
transferase) activity. The recent identification of two
bilirubin transferase isoforms with identical carboxyl termini (Ritter, J. K., J. M. Crawford, and I. S. Owens. 1991. J. Biol. Chem. 266:1043-1047) led to the discovery of a unique locus, UGT1, which encodes a family of
UDP-glucuronosyltransferase isozymes, including the two
bilirubin forms (Ritter, J. K., F. Chen, Y. Y. Sheen, H. M. Tran, S. Kimura, M. T. Yeatman, and I. S. Owens. 1992. J. Biol. Chem. 267:3257-3261). The UGT1 locus features a complex of six overlapping transcriptional units encoding
transferases, each of which shares the four most 3' exons (2, 3, 4, and 5) specifying the 3' half of the
transferase coding regions (condons 289-533) and the entire
3' untranslated region of each
mRNA. This gene model predicts that a single critical mutation in any of these four "common" exons may inactivate the entire family of encoded
transferases. In agreement with this prediction, we show here that in the first CN type I individual analyzed (patient F.B.), a 13-bp deletion has occurred in exon 2. Analysis of product generated by the polymerase chain reaction and genomic
DNA demonstrated that F.B. is homozygous for the defective allele (UGT1*FB), and that the consanguineous parents are both heterozygotic at this locus. The mutation is predicted to result in the synthesis of severely truncated
bilirubin transferase isozymes that are lacking a highly conserved sequence in the carboxyl-terminus and the characteristic membrane (endoplasmic reticulum)-anchoring segment of the
protein molecule.