Mutation of UGT1A1 gene in a case of Crigler-Najjar syndrome type II.

Abstract

TO THE EDITOR: Crigler-Najjar syndrome type II is a moderate-to-severe familial unconjugated hyperbilirubinemia. Several kinds of mutations of the bilirabin UDP-glycosyltransferase gene (UGT1A1) have been reported in patients with this disorder: homozygous missense mutations (L15R, L175E, R209W, and Q331R), compound heterozygous mutation (G71R and Y486D), a stop codon (Q331X), and frameshift mutation (deletion of nucleotide 973) (1, 2, 3). In the present study, we report for the first time the presence of homozygous Y486D mutation in a case of Crigler-Najjar syndrome type II. The patient was a Japanese man 37-yr old who consulted to Fukuchiyama Central Hospital because of severe jaundice. The patient had presented with jaundice since childhood. His mother and two brothers were also icteric. Physical examination revealed severe icterus without anemia. Laboratory studies revealed serum concentrations of bilirabin of 136.8 mol/L, direct-reacting bilirabin 13.7 mol/L, AST 23 IU/L, ALT 19 IU/L, ALP 201 IU/L, 15-min plasma retention of ICG 8.2%, red blood cell count of 466 104/mm3 and haptoglobin 84 mg/dl. Genomic DNA was extracted from peripheral blood leukocytes by standard methods. Amplification of the five exons and the promoter region of the UGT1A1 gene was carried out by PCR as previously described (4, 5). Direct sequencing of PCR products was performed using the ABI PRISM genetic analyzer (PE Applied Biosystems, Foster City, CA). Gene analysis revealed that the patient was homozygous for a missense mutation of Y486D (T G in nucleotide 1456) of exon 5; gene analysis also showed a normal TATA box (A[TA]6TAA). No additional mutation was seen in exon 1–4. These findings in our present case showed that homozygous Y486D causes Crigler-Najjar syndrome type II. In agreement with this, Yamamoto et al. reported a 92.4% decrease in UGT1A1 activity after transfection of COS7 cells with the homozygous Y486D-mutated gene (6). Heterozygous Y486D mutations of UGT1A1 have also been reported in patients with Gilbert's syndrome; we have experienced three patients with Gilbert's syndrome with heterozygous Y486D presenting mild hyperbilirubinemia (the serum concentrations of bilirubin in these patients were 76.0, 42.8, and 20.5 mol/L). In addition, Maruo et al. reported a case of Gilbert's syndrome in a female patient with homozygous Y486D mutation (the serum bilirubin concentration of their patient was 44.4 mol/L) (7). It is known that the serum level of bilirubin is higher in men than in women; the sex difference and other unidentified factors may explain the high serum level of bilirubin in our patient compared with that in the case reported by Maruo et al. Nevertheless, the present case showed for the first time that homozygous Y486D mutation may also cause Crigler-Najjar syndrome type II.