No abstract

Crigler-Najjar syndrome, type I is a heterogeneous disorder that may result from mutations of various regions of the bilirubin-UDP-glucuronosyltransferase gene complex that encodes two bilirubin-UDP-glucuronosyltransferase isoforms and a phenol-UDP-glucuronosyltransferase isoform in the human liver. The two bilirubin-UDP-glucuronosyltransferase messenger RNAs and the phenol-UDP-glucuronosyltransferase messenger RNA have identical 3' regions derived from four consecutive exons. The 5' region of each messenger RNA is unique and is derived from distinct single exons. By screening a human genomic library with probes corresponding to various regions of the messenger RNAs, we have isolated five cosmid clones containing overlapping segments of this large gene complex that spans at least 84 kb of the human genome. To facilitate the amplification of each exon by polymerase chain reaction and their adjacent splice junctions, we have delineated the intron-exon boundaries of the four common region exons and the two single exons that encode the unique regions of the two bilirubin-UDP-glucuronosyltransferase isoforms and have described sequences of the regions flanking each exon. All exons encoding the two bilirubin-UDP-glucuronosyltransferase isoforms and their splice junctions were amplified from the DNA of two control subjects and a Crigler-Najjar syndrome, type I patient. The DNA from the Crigler-Najjar syndrome, type I patient revealed a point mutation in exon 3 (a common region exon) resulting in a stop codon. RNA blot showed that the two bilirubin-UDP-glucuronosyltransferase messenger RNAs in the liver of the Crigler-Najjar syndrome, type I patient were of normal length but were reduced in concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The VLDL receptor (VLDLR) is a member of the LDL receptor family. The VLDLR was hypothesized to mediate fatty acid entry into peripheral tissues, on the basis of its expression in tissues that are active in fatty acid metabolism and its capacity to bind apolipoprotein-E-rich VLDL in vitro. This hypothesis initially proved difficult to confirm, because VLDLR-knockout mice were reported to display normal plasma lipid levels. Moreover, studies in VLDLR-knockout mice that were also deficient in a second LDL receptor family member, the apolipoprotein E receptor 2, indicated a role for the VLDLR in neuronal migration during brain development. However, in accordance with what the term VLDLR suggests, recent studies using VLDLR-deficient and transgenic mice have provided compelling evidence that the VLDLR does indeed play a role in VLDL-triglyceride metabolism, and that it is important for triglyceride storage in the adipocyte.