Bilirubin metabolic disordersnew课件.pptVIP

Bilirubin metabolic disorders;Objectives:;Formation of bilirubin;The bilirubin is then transported to the liver where it reacts with a solubilizing sugar glucuronic acid. Soluble form of bilirubin (conjugated) is excreted into the bile. ;Heme degradation;Genetic of bilirubin metabolic disorders;Gilberts syndrome ; Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum. ;Molecular basis of Gilberts syndrome;;Molecular basis of Gilberts syndrome;Gilberts syndrome classed as a minor inborn error of metabolism. Approximately 9% of the population is homozygous, and 42% is heterozygous, with a gene frequency of 0.3. nearly all patients had normal coding regions for UGT1A1 but were homozygous for the insertion of an extra TA (i.e., A[TA]7TAA rather than A[TA]6TAA) in the promoter region of the first exon ;Structural organization of the human UGT1 gene complex. This large complex on chromosome 2 contains at least 13 substrate-specific first exons (A1, A2, etc.). Since four of these are pseudogenes, nine UGT1 isoforms with differing substrate specificities are expressed. Each exon 1 has its own promoter and encodes the amino-terminal substrate-specific ~286 amino acids of the various UGT1-encoded isoforms, and common exons 2–5 that encode the 245 carboxyl-terminal amino acids common to all of the isoforms. mRNAs for specific isoforms are assembled by splicing a particular first exon such as the bilirubin-specific exon A1 to exons 2 to 5. The resulting message encodes a complete enzyme, in this particular case bilirubin-UDP-glucuronosyltransferase (UGT1A1). Mutations in a first exon affect only a single isoform. Those in exons 2–5 affect all enzymes encoded by the UGT1 complex.;Signs and symptoms;CRIGLER-NAJJAR SYNDROME, TYPE I; CONGENITAL NONHEMOLYTIC JAUNDICEType I Crigler-Najjar syndrome;;More than 30 different genetic lesions of UGT1A1 responsible for CN-I have been identified, including deletions, insertions, alteration