Mutations in the promoter region of the aldolase B gene that cause hereditary fructose intolerance. J Inherit Metab Dis

Molecular Biology, Cell Biology, and Biochemistry Program, Boston, MA 02215, USA.
Journal of Inherited Metabolic Disease (Impact Factor: 3.37). 09/2010; 33(6):715-25. DOI: 10.1007/s10545-010-9192-5
Source: PubMed


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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Available from: Dean R Tolan,
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    • "Our data indicate the importance of extending sequence analysis to the entire coding sequence and intron/exon boundaries of the ALDOB gene of suspected HFI patients, in accordance with recent reports (Esposito et al. 2010, Coffee and Tolan 2010). The heterozygous status or the mutation negative status for the most common mutations do not exclude the affected status as such patients should be further investigated at the molecular level. "
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    ABSTRACT: Mutations in the ALDOB gene impair the activity of the hepatic aldolase B enzyme, causing hereditary fructose intolerance (HFI), an inherited autosomic recessive disease of carbohydrate metabolism, that can result in hypoglycemia, liver and kidney failure, coma, and death. Noninvasive diagnosis is possible by identifying mutant ALDOB alleles in suspected patients. We report the genetic characterization of a cohort of 18 HFI Caucasian patients, based on PCR-sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA), with the identification of two novel genetic lesions: a small duplication c.940_941dupT (p.Trp314fsX22) and a large deletion encompassing the promoter region and exon 1. MLPA and long range-PCR (LR-PCR) also identified the recently reported g.7840_14288del6448 allele with a surprisingly high frequency (11%) within our patients' cohort. The most common p.Ala150Pro (44%), p.Ala175Asp (19%), p.Asn335Lys (8%), and/or the known c.360-363del4 (5%), p.Tyr204X (2.8%), IVS6 -2A>G (2.8%) mutant alleles were identified in 14 patients at a homozygous or compound-heterozygous level. The integration of PCR-sequencing analysis with exon-dosage tools [MLPA and quantitative fluorescent multiplex-PCR (QFM-PCR)] led to the full genotyping of patients within our cohort and to the identification of the new deletion encompassing the promoter region and exon 1.
    01/2012; 6:31-7. DOI:10.1007/8904_2012_125
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    • "Alteration in the food chain by a Western practice dramatically increased the intake of high fructose corn syrup resulting in increased prevalence of fructose intolerance. Research suggests that expression of previously silent alleles occurred with altered fructose intake (Ali and Cox, 1995; Coffee and Tolan, 2010). Dietary management reducing specific protein intake was established to prevent severe mental deficits from resulting from phenylketonuria (PKU), a genetic inability to metabolize the amino acid phenylalanine. "

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