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Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Hereditary fructose intolerance (HFI) is a potentially fatal inherited metabolic disease caused by a deficiency of aldolase B activity in the liver and kidney. Over 40 disease-causing mutations are known in the protein-coding region of ALDOB. Mutations upstream of the protein-coding portion of ALDOB are reported here for the first time. DNA sequence analysis of 61 HFI patients revealed single base mutations in the promoter, intronic enhancer, and the first exon, which is entirely untranslated. One mutation, g.−132G>A, is located within the promoter at an evolutionarily conserved nucleotide within a transcription factor-binding site. A second mutation, IVS1+1G>C, is at the donor splice site of the first exon. In vitro electrophoretic mobility shift assays show a decrease in nuclear extract-protein binding at the g.−132G>A mutant site. The promoter mutation results in decreased transcription using luciferase reporter plasmids. Analysis of cDNA from cells transfected with plasmids harboring the IVS1+1G>C mutation results in aberrant splicing leading to complete retention of the first intron (~5 kb). The IVS1+1G>C splicing mutation results in loss of luciferase activity from a reporter plasmid. These novel mutations in ALDOB represent 2% of alleles in American HFI patients, with IVS1+1G>C representing a significantly higher allele frequency (6%) among HFI patients of Hispanic and African-American ethnicity.

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Acknowledgements

The authors would like to thank Marilyn McCorn-St. Fleur, Michelle Garcia, Rachel Gibbons, and Taliesin Lenhart for their contributions in performing DNA sequence analysis. We would like to thank Dr. Harvey Levy for critical reading of the manuscript. This work was supported in part by National Institutes of Health grant DK-065089 (to DRT).

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Authors and Affiliations

  1. Molecular Biology, Cell Biology, and Biochemistry Program, Boston, MA, 02215, USA

    Erin M. Coffee & Dean R. Tolan

  2. Biology Department, Boston University, 5 Cummington Street, Boston, MA, 02215, USA

    Dean R. Tolan

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  1. Erin M. Coffee
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  2. Dean R. Tolan
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Correspondence to Dean R. Tolan.

Additional information

Communicated by: Guy Besley

Competing interest: None declared

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Fig. 1S

Construction of pProm2 for transient transfection assays A fragment of DNA from position –264 to +2870 and a fragment of DNA from position +4795 to +4890 were PCR amplified from wild-type DNA using primers with Xma I sites and Bgl II sites embedded within, respectively. Each fragment was digested with the appropriate restriction enzyme. The smaller, exon 2-containing fragment was cloned into pGL3-basic at the Bgl II site creating pGL3-100. The larger, promoter-containing fragment was cloned into pGL3-100 at the Xma I site creating pProm2. The G>A point mutant at g.–132 was introduced by site-directed mutagenesis creating p-132G>A

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Coffee, E.M., Tolan, D.R. Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. J Inherit Metab Dis 33, 715–725 (2010). https://doi.org/10.1007/s10545-010-9192-5

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  • DOI: https://doi.org/10.1007/s10545-010-9192-5

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