Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: Correlation of genotype to phenotype

Ajit Kadakol, Siddhartha S. Ghosh, Baljit S. Sappal, Girish Sharma, Jayanta Roy-Chowdhury, Namita Roy Chowdhury

Research output: Contribution to journalArticle

276 Citations (Scopus)

Abstract

Uridine-diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile. Bilirubin-UGT1 (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin. Lesions in the gene encoding bilirubin-UGT1, lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler-Najjar syndrome type-1 (CN-1) and type 2 (CN-2), respectively. Inactivation of the enzyme leads to accumulation of unconjugated bilirubin in the serum. Severe hyperbilirubinemia seen in CN-1 can cause bilirubin encephalopathy (kernicterus). Kernicterus can be fatal or may leave behind permanent neurological sequelae. Here, we have compiled more than 50 genetic lesions of UGT1A1 that cause CN-1 (including 9 novel mutations) or CN-2 (including 3 novel mutations) and have presented a correlation of structure to function of UGT1A1. In contrast to Crigler-Najjar syndromes, Gilbert syndrome is a common inherited condition characterized by mild hyperbilirubinemia. An insertional mutation of the TATAA element upstream to UGT1A1 results in a reduced level of expression of the gene. Homozygosity for the variant promoter is required for Gilbert syndrome, but not sufficient for manifestation of hyperbilirubinemia, which is partly dependent on the rate of bilirubin production. Several structural mutations of UGT1A1, for example, a G71R substitution, have been reported to cause mild reduction of UGT activity toward bilirubin, resulting in mild hyperbilirubinemia, consistent with Gilbert syndrome. When the normal allele of a heterozygote carrier for a Crigler-Najjar type structural mutation contains a Gilbert type promoter, intermediate levels of hyperbilirubinemia, consistent with the diagnosis of CN-2, may be observed. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish (US)
Pages (from-to)297-306
Number of pages10
JournalHuman Mutation
Volume16
Issue number4
DOIs
StatePublished - 2000

Fingerprint

Crigler-Najjar Syndrome
Gilbert Disease
Glucuronosyltransferase
Uridine
Genetic Association Studies
Hyperbilirubinemia
Bilirubin
Kernicterus
Mutation
Enzymes
Glucuronic Acid
Heterozygote
Bile
Protein Isoforms
Alleles
Gene Expression
Serum

Keywords

  • Bilirubin UDP-glucuronosyltransferase
  • Crigler-Najjar syndrome
  • Gilbert syndrome
  • UGT1
  • UGT1A1
  • Unconjugated hyperbilirubinemia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes : Correlation of genotype to phenotype. / Kadakol, Ajit; Ghosh, Siddhartha S.; Sappal, Baljit S.; Sharma, Girish; Roy-Chowdhury, Jayanta; Chowdhury, Namita Roy.

In: Human Mutation, Vol. 16, No. 4, 2000, p. 297-306.

Research output: Contribution to journalArticle

Kadakol, Ajit ; Ghosh, Siddhartha S. ; Sappal, Baljit S. ; Sharma, Girish ; Roy-Chowdhury, Jayanta ; Chowdhury, Namita Roy. / Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes : Correlation of genotype to phenotype. In: Human Mutation. 2000 ; Vol. 16, No. 4. pp. 297-306.
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abstract = "Uridine-diphosphoglucuronate glucuronosyltransferases (UGTs) are a family of enzymes that conjugate various endogenous and exogenous compounds with glucuronic acid and facilitate their excretion in the bile. Bilirubin-UGT1 (UGT1A1) is the only isoform that significantly contributes to the conjugation of bilirubin. Lesions in the gene encoding bilirubin-UGT1, lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler-Najjar syndrome type-1 (CN-1) and type 2 (CN-2), respectively. Inactivation of the enzyme leads to accumulation of unconjugated bilirubin in the serum. Severe hyperbilirubinemia seen in CN-1 can cause bilirubin encephalopathy (kernicterus). Kernicterus can be fatal or may leave behind permanent neurological sequelae. Here, we have compiled more than 50 genetic lesions of UGT1A1 that cause CN-1 (including 9 novel mutations) or CN-2 (including 3 novel mutations) and have presented a correlation of structure to function of UGT1A1. In contrast to Crigler-Najjar syndromes, Gilbert syndrome is a common inherited condition characterized by mild hyperbilirubinemia. An insertional mutation of the TATAA element upstream to UGT1A1 results in a reduced level of expression of the gene. Homozygosity for the variant promoter is required for Gilbert syndrome, but not sufficient for manifestation of hyperbilirubinemia, which is partly dependent on the rate of bilirubin production. Several structural mutations of UGT1A1, for example, a G71R substitution, have been reported to cause mild reduction of UGT activity toward bilirubin, resulting in mild hyperbilirubinemia, consistent with Gilbert syndrome. When the normal allele of a heterozygote carrier for a Crigler-Najjar type structural mutation contains a Gilbert type promoter, intermediate levels of hyperbilirubinemia, consistent with the diagnosis of CN-2, may be observed. (C) 2000 Wiley-Liss, Inc.",
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