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Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1.

Authors: Gantla, S  Bakker, CT  Deocharan, B  Thummala, NR  Zweiner, J  Sinaasappel, M  Roy Chowdhury, J  Bosma, PJ  Roy Chowdhury, N 
Citation: Gantla S, etal., Am J Hum Genet. 1998 Mar;62(3):585-92.
Pubmed: (View Article at PubMed) PMID:9497253
DOI: Full-text: DOI:10.1086/301756

Crigler-Najjar syndrome type 1 (CN-1) is a recessively inherited, potentially lethal disorder characterized by severe unconjugated hyperbilirubinemia resulting from deficiency of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. In all CN-1 patients studied, structural mutations in one of the five exons of the gene (UGT1A1) encoding the uridinediphosphoglucuronate glucuronosyltransferase (UGT) isoform bilirubin-UGT1 were implicated in the absence or inactivation of the enzyme. We report two patients in whom CN-1 is caused, instead, by mutations in the noncoding intronic region of the UGT1A1 gene. One patient (A) was homozygous for a G-->C mutation at the splice-donor site in the intron, between exon 1 and exon 2. The other patient (B) was heterozygous for an A-->G shift at the splice-acceptor site in intron 3, and in the second allele a premature translation-termination codon in exon 1 was identified. Bilirubin-UGT1 mRNA is difficult to obtain, since it is expressed in the liver only. To determine the effects of these splice-junction mutations, we amplified genomic DNA of the relevant splice junctions. The amplicons were expressed in COS-7 cells, and the expressed mRNAs were analyzed. In both cases, splice-site mutations led to the use of cryptic splice sites, with consequent deletions in the processed mRNA. This is the first report of intronic mutations causing CN-1 and of the determination of the consequences of these mutations on mRNA structure, by ex vivo expression.

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RGD Object Information
RGD ID: 1600438
Created: 2007-03-08
Species: All species
Last Modified: 2007-03-08
Status: ACTIVE



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