TY - JOUR
T1 - Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes
T2 - Correlation of genotype to phenotype
AU - Kadakol, Ajit
AU - Ghosh, Siddhartha S.
AU - Sappal, Baljit S.
AU - Sharma, Girish
AU - Chowdhury, Jayanta Roy
AU - Chowdhury, Namita Roy
PY - 2000
Y1 - 2000
N2 - 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.
AB - 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.
KW - Bilirubin UDP-glucuronosyltransferase
KW - Crigler-Najjar syndrome
KW - Gilbert syndrome
KW - UGT1
KW - UGT1A1
KW - Unconjugated hyperbilirubinemia
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U2 - 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z
DO - 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z
M3 - Review article
C2 - 11013440
AN - SCOPUS:0033799997
SN - 1059-7794
VL - 16
SP - 297
EP - 306
JO - Human Mutation
JF - Human Mutation
IS - 4
ER -