Association of the widespread A149P hereditary fructose intolerance mutation with newly identified sequence polymorphisms in the aldolase B gene.
Hereditary fructose intolerance (HFI) is a potentially fatal autosomal recessive disease resulting from the catalytic deficiency of fructose 1-phosphate aldolase (aldolase B) in fructose-metabolizing tissues. The A149P mutation in exon 5 of the aldolase B gene, located on chromosome 9q21.3-q22.2, is widespread and the most common HFI mutation, accounting for 57% of HFI chromosomes. The possible origin of this mutation was studied by linkage to polymorphisms within the aldolase B gene. DNA fragments of the aldolase B gene containing the polymorphic marker loci from HFI patients homozygous for the A149P allele were amplified by PCR. Absolute linkage to a common PvuII RFLP allele was observed in 10 A149P homozygotes. In a more informative study, highly heterozygous polymorphisms were detected by direct sequence determination of a PCR-amplified aldolase B gene fragment. Two two-allele, single-base-pair polymorphisms, themselves in absolute linkage disequilibrium, in intron 8 (C at nucleotide 84 and A at nucleotide 105, or T at 84 and G at 105) of the aldolase B gene were identified. Mendelian segregation of these polymorphisms was confirmed in three families. Allele-specific oligonucleotide (ASO) hybridizations with probes for both sequence polymorphisms showed that 47% of 32 unrelated individuals were heterozygous at these loci; the calculated PIC value was .37. Finally, ASO hybridizations of PCR-amplified DNA from 15 HFI patients homozygous for the A149P allele with probes for these sequence polymorphisms revealed absolute linkage disequilibrium between the A149P mutation and the 84T/105G allele. These results are consistent with a single origin of the A149P allele and subsequent spread by genetic drift.
Brooks
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CC
Department of Biology, Boston University, MA 02215.
Tolan
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D001345:Autoradiography; D001483:Base Sequence; D016009:Chi-Square Distribution; D002899:Chromosomes, Human, Pair 9; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D016521:Electrophoresis, Gel, Pulsed-Field; D005633:Fructose Intolerance / Q000235:genetics*; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D006801:Humans; D015810:Linkage Disequilibrium; D008540:Meiosis; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length
D005819:Genetic Markers; D015345:Oligonucleotide Probes; D005634:Fructose-Bisphosphate Aldolase