Diseases associated with impaired bilirubin metabolism

Of the hereditary disorders of bilirubin metabolism, the Kriegler-Nayar type I and Gilbert syndromes are most frequently observed. Syndromes of Kriegger-Nayyar type II, Dabin-Johnson( * 237500, a defect of the tubule transporter gene of organic anions CMOAT, 10q24 [* 601107], p) and Rotor( * 237450, conjugated hyperbilirubinemia type I, p) are very rare diseases.

The structure of the uridine diphosphate glucuronyltransferase gene( UDPGT) is complex. In all forms of UDFGT, the constant components are

Fig. The structure of the UDFGT gene [Sherlock Sh., Dulley J., 1999]

Fig. The structure of the UDFGT gene [Sherlock S., Dully J., 1999]

exons 2-5 at the 3-end of the DNA of the gene. For gene expression, one or more first exons must be involved. Thus, in the formation of isoenzymes UDFGT 1 * 1, the exon 1 sequences are determined by the substrate specificity and the properties of the enzymes. Further expression of UDPGT 1 * 1 also depends on the promoter region at the 5-end associated with each of the first exons. The promoter region contains the TATAA sequence.

Details of the structure of the gene are important for understanding the pathogenesis of Gilbert and Kriegler-Nayar syndromes.

The genetic defect is based on the Gilbert syndrome( # 143500, UGT1A1, 1q21-q23) - the presence of an additional dinucleotide TA on the promoter site of the gene encoding UDFGT 1 * 1, which leads to the formation of the [A( TA), TAA] region. Elongation of the promoter sequence of nucleotides disrupts the binding of the transcription factor IID, which leads to a decrease in the formation of UDPGT 1.

In the Krigler-Nayyar type I syndrome( 218800, p), the genetic defect is localized in one of the 5 exons( 1A-5) of the UDPGT 1 * 1 geneleads to a lack of activity of the conjugating enzyme in the liver.

In Type II Criegler-Nayyar syndrome( 143500) mutations in exons 1A-5 of the UDFGT 1 * 1 gene are also detected, however, the liver has a residual activity of the enzyme, therefore bilirubinemia is less high than in Type I Kriger-Nayyar syndrome. Analysis of the UDPGT gene1 * 1 suggests that mixed heterozygosity exists in such patients: in one of the alleles, the TATAA mutation inherent in Gilbert's syndrome, and in the other, the mutation inherent in Kriegger-Nayyar syndrome.