Genetic background of constitutional unconjugated hyperbilirubinemia

Crigler-Najjar syndrome (types I and II) and Gilbert's syndrome are familial disorders associated with severe to mild unconjugated hyperbilirubinemia. In these conditions, the activity of bilirubin UDP-glucuronosyltransferase (UGT1*1), which is located in the hepatocyte endoplasmic reticulum, is defective, and severely and moderately decreased, respectively. UGT1*1 is derived from one of the UGT1 genes. It has a promoter containing a TATA box and consists of exon 1A (which is one of the individual first exons) and common exons 2-5. UGT1*1 mRNA is formed by differential splicing of these exons. In recent years, gene analysis of these syndromes has been carried out, and genetic abnormalities have been clarified. Homozygous nonsense mutations, mis-sense mutations, and other relevant mutations of exons 1A-5 have been reported in almost all of the patients with Crigler-Najjar syndrome type I, while mainly homozygous mis-sense mutations of exons 1A, 2, and 5 have been reported in type II patients. Almost all patients with this syndrome (types I and II) show autosomal recessive inheritance. On the other hand, some patients with Gilbert's syndrome show heterozygous mis-sense mutations in exons 1A, 4, and 5, while others show homozygous 2-base pair-insertion mutation (TA) into the TATA box in the promoter region [A(TA)(7)TAA; normal: A(TA)(6)TAA]. The pattern of inheritance can be autosomal recessive or autosomal dominant. It has also been clarified that enzyme activity is lowered to about 30% (rather than 50%) by heterozygous mutations of the coding region, because of the occurrence of dominant negative mutation based on subunit-structure of the enzyme.