Allelic heterogeneity in adult hereditary fructose intolerance. Detection of structural mutations in the aldolase B molecule.

Hereditary fructose intolerance (HFI) is a disorder of visceral carbohydrate metabolism which is transmitted as a recessive character of moderate to high gene prevalence. The condition is caused by enzymic deficiency of aldolase B and is associated with the synthesis of inactive enzyme protein. The molecular structure of aldolase B was examined in tissue samples from four adult patients who were the offspring of non-consanguineous unions. Titration of aldolase protein, by radioimmunoassay, showed that antibody recognition of the inactive enzyme was attenuated differently in two unrelated HFI patients. The existence of separate structural lesions was confirmed by protein blotting and immunodetection of enzyme subunits after sodium dodecyl sulphate/polyacrylamide electrophoresis. In one patient the subunit size was identical to wild type (Mr 38,000) and in the other, a single faint band (Mr 39,000) was identified. Radioimmunotitration studies, in two affected offspring of this latter patient by a proven HFI carrier, also revealed differences in antibody recognition. Segregation of different mutant alleles within this kindred demonstrates heterogeneity in HFI occurring at the same genetic locus. Variations in apparent immunoreactivity of aldolase B in HFI are thus related to overt modification of enzyme subunits and indicate that the disorder results principally from structural rather than regulatory mutations in the aldolase B gene.