Severe hyperbilirubinaemia in a Chinese girl with type I Crigler–Najjar syndrome: First case ever reported in Mainland China

Abstract

Jaundice is common in ethnic Chinese infants, but to our knowledge Crigler-Najjar syndrome (CN syndrome) type I has never been reported in China. A Chinese girl with severe jaundice was recently diagnosed to have CN syndrome type I by analyzing the bilirubin-uridinediphospho (UDP)-glucuronosyltransferase gene (UGT1A1). The patient was homozygous for a nonsense mutation that replaced glutamine (CAG, amino acid 239) with stop codon (TAG) at nucleotide number 715 (715C-->T) in exon 1. No mutation was found in exons 2-5. Her parents were heterozygous for the same mutant. The patient had an average bilirubin level of 300-500 mumol/L and a peak of 701 mumol/L. Daily phototherapy for 15 h was required to keep the bilirubin levels within 280-320 mumol/L. The unconjugated hyperbilirubinaemia apparently resulted from homozygous nonsense mutation of UGT1A1, which could completely abolish the UGT activity towards bilirubin (hepatic glucuronidation) and result in CN syndrome type I. Identification of the genetic defect is very useful for gene therapy, especially for DNA/RNA chimera therapy, and can be used as an antenatal screening test to identify the affected offsprings.

Spectrum of UGT1A1 Variations in Chinese Patients with Crigler-Najjar Syndrome Type II

“…Nine of the 11 cases carried variations that are reported here for the first time in CNS-II patients (patients 3 to 11). The two variants predicted to cause truncation of UGT (M418fsX423 variant and Q239X variant) were also previously detected in CNS-I patients [ 13 , 14 ]. The Y486D variant has been shown to lower the bilirubin UGT activity by more than 90% [ 15 ] and was detected only in CNS-II patients.…”

Uridine diphosphoglucuronosyltransferase pharmacogenetics and cancer

“…In Asian populations, several exon 1 mutations such as UGT1A1*6 (G71R), *7 (Y486D) and *27 (P229Q) contribute significantly to mild to moderate hyperbilirubinemia. The two most recently reported mutations are a 715C-T nucleotide change in exon 1, leading to a truncated protein (Nong et al, 2005), and a 686C-T nucleotide change in exon 1 that causes a P229L protein change (Kaniwa et al, 2005). Table 2 summarizes some UGT1A1 mutations reported to date that have been characterized in pharmacogenetic studies.…”

A homozygous mutation in a Chinese man with Crigler–Najjar syndrome type II and a family genetic analysis

“…Many molecular defects, which harm the glucuronidation of bilirubin, have been found in the UGT1A1 gene of CN patients. Most findings, however, come from Western countries and Japan, but we could not find any molecular study in Chinese CN patients 6 …”

“…In the milder phenotype of CN-II, however, the homozygosity of the missense mutations seems to be the main defect, while the rarer types are results of the genetic compound of both nonsense (frameshift) and missense mutations. It can also be from an interaction between missense mutations and a homozygous TA insertion in the TATAA promoter elements, A(TA) 7 , TAA, which replace the normal A(TA) 6 , TAA. 11 For example, it was detected in the first exon of UGT1A1 that there are T→G (Leu15Arg) at codon 44, T→A (Leu157Gln) at codon 524, C→T (Arg209Trp) at codon 625, G→A (Gly71Arg) at codon 211 and C→A (Pro229Gln) at codon 686.…”

“…Most findings, however, come from Western countries and Japan, but we could not find any molecular study in Chinese CN patients. 6 Recently, we received a 22-year-old man with CN-II and performed a genetic analysis of his family. A single homozygous mutation in the UGT1A1 gene was found.…”