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

Shailaja Gantla, Conny T.M. Bakker, Bishram Deocharan, Narsing R. Thummala, Jeffry Zweiner, Maarten Sinaasappel, Jayanta Roy Chowdhury, Piter J. Bosma, Namita Roy Chowdhury

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50 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)585-592
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number3
StatePublished - Mar 1998

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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