Abstract
Crigler–Najjar Syndrome type II (CNS-II) is an autosomal recessive hereditary condition of unconjugated hyperbilirubinemia without hemolysis, with bilirubin levels ranging from 102.6 μmol/L to 342 μmol/L. CNS-II is caused by a deficiency of UDP-glucuronyl transferase (UGT), which is encoded by the UDP-glucuronyl transferase 1A1 gene (UGT1A1). In East Asian populations, the compound homozygous UGT1A1 G71R and Y486D variants are frequently observed in cases with bilirubin levels exceeding 200 μmol/L. In this study, we investigated the spectrum of UGT1A1 variations in Chinese CNS-II patients. We sequenced the enhancer, promoter, and coding regions of UGT1A1 in 11 unrelated Chinese CNS-II patients and 80 healthy controls. Nine of these patients carried variations that are here reported for the first time in CNS-II patients, although they have been previously reported for other types of hereditary unconjugated hyperbilirubinemia. These individual variations have less influence on UGT activity than do the compound homozygous variation (combination of homozygous G71R variant and Y486D variant). Therefore, we propose that the spectrum of UGT1A1 variations in CNS-II differs according to the bilirubin levels.
Highlights
Inherited unconjugated hyperbilirubinemia is categorized as Gilbert Syndrome (GS; OMIM: 143500), Crigler–Najjar Syndrome type I (CNS-I; OMIM: 218800), or Crigler–Najjar Syndrome type II (CNS-II; OMIM: 606785), depending on the total bilirubin (TB) levels: the TB levels range from 17.1 μmol/L to 102.6 μmol/L, 102.6 μmol/L to 342 μmol/L, and 342 μmol/L to 769.5 μmol/L in GS, CNS-II, and CNS-I, respectively
We reviewed Crigler–Najjar case reports in NCBI PubMed, EMBASE, HGMD (CM062020, CM062020, CM941960, CD941964, CM931125, CM961403, CM972924, CM983519, CM002648, CM002649, CM002415, CD002537, CD014669, CM022853, CM051658, CM051659, CM051661, CM051662, CM051665, CM051666, CS051705, CS051706, CM066253, CM062021, CM062019, CD062241, CM067485, CM067484, CM100072, CM100073, CD100074, CM098937), OMIM (191740) databases between January 1992 and November 2014 and found that the compound homozygous G71R variant and Y486D variant were frequently detected in East Asian CNS-II patients whose bilirubin levels were greater than 200 μmol/L (10/13) [6,7,8,9,10,11,12]
We investigated the spectrum of UDP-glucuronyl transferase 1A1 gene (UGT1A1) variations in 11 Chinese CNS-II patients and nine variants were identified
Summary
Inherited unconjugated hyperbilirubinemia is categorized as Gilbert Syndrome (GS; OMIM: 143500), Crigler–Najjar Syndrome type I (CNS-I; OMIM: 218800), or Crigler–Najjar Syndrome type II (CNS-II; OMIM: 606785), depending on the total bilirubin (TB) levels: the TB levels range from 17.1 μmol/L to 102.6 μmol/L, 102.6 μmol/L to 342 μmol/L, and 342 μmol/L to 769.5 μmol/L in GS, CNS-II, and CNS-I, respectively. CNS-I can be fatal due to kernicterus, which does not respond to phenobarbital treatment. The bilirubin level in CNS-II can be controlled by phenobarbital treatment to avoid the neurological damage caused by unconjugated bilirubin [1]. Liposoluble unconjugated bilirubin is glucuronidated to form hydrosoluble conjugated bilirubin by UDP-glucuronyl transferases (UGT) [2]. This enzyme is encoded by the UDP-glucuronyl transferase 1A1 gene (UGT1A1), which forms part of a complex gene locus (UGT1A gene complex). UGT1A encodes a number of UGTs by alternative splicing, each with various substrate preferences [3]
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