Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance
- 30 September 2010
- journal article
- research article
- Published by Wiley in Journal of Inherited Metabolic Disease
- Vol. 33 (6), 715-725
- https://doi.org/10.1007/s10545-010-9192-5
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.Funding Information
- National Institutes of Health (DK‐065089)
This publication has 51 references indexed in Scilit:
- Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American populationJournal of Inherited Metabolic Disease, 2009
- A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotypeBMC Medical Genetics, 2009
- The mammalian nonsense-mediated mRNA decay pathway: To decay or not to decay! Which players make the decision?FEBS Letters, 2009
- Transcription Factors and Aldolase B Gene Expression in Microdissected Renal Proximal Tubules and Derived Cell LinesExperimental Cell Research, 1995
- Characterization of Recombinant Human Aldolase B and Purification by Metal Chelate ChromatographyBiochemical and Biophysical Research Communications, 1995
- Iatrogenic deaths in hereditary fructose intolerance.Archives of Disease in Childhood, 1993
- Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North AmericansBiochemical Medicine and Metabolic Biology, 1992
- Expression of the rat aldolase B gene: A liver-specific proximal promoter and an intronic activatorBiochemical and Biophysical Research Communications, 1991
- Disruption of a C/EBP binding site in the factor IX promoter is associated with haemophilia BNature, 1990
- Application of Endonuclease Mapping to the Analysis and Prenatal Diagnosis of Thalassemias Caused by Globin-Gene DeletionThe New England Journal of Medicine, 1978