Inheritance of Lysosomal Acid β-Galactosidase Activity and Gangliosides in Crosses of DBA/2J and Knockout Mice

Abstract

GM1 gangliosidosis is a progressive neurodegenerative disease caused by deficiencies in lysosomal acid β-galactosidase (β-gal) and involves accumulation and storage of ganglioside GM1 and its asialo form (GA1) in brain and visceral tissues. Similar to the infantile/juvenile human disease forms, B6/129Sv β-gal knockout (ko) mice express residual tissue β-gal activity and significant elevations of brain GM1, GA1, and total gangliosides. Previous studies suggested that inbred DBA/2J (D2) mice may model a mild form of the human disease since total brain ganglioside and GM1 concentration is higher while β-gal specific activity is lower (by 70–80%) in D2 mice than in inbred C57BL/6J (B6) mice and other mouse strains. A developmental genetic analysis was conducted to determine if the genes encoding β-gal (Bgl) in the D2 and the ko mice were functionally allelic and if the reduced brain β-gal activity in D2 mice could account for elevations in total brain gangliosides and GM1. Crosses were made between D2 mice homozygous for the Bgl ^d allele (d/d), and either B6/129Sv mice heterozygous for the Bgl ⁺ allele (+/−) or homozygous for the ko Bgl ⁻ allele (−/−) to generate d−/+ and d−/− mice. Specific β-gal activity (nmol/mg protein/h) showed additive inheritance in brain, liver, and kidney at juvenile (21 days) and adult (255 days) ages with the d−/− mice having only about 16% of the β-gal activity as that in the +/+ mice. These results indicate that the Bgl genes in the D2 and the ko mice are noncomplementing functional alleles. However, the d−/− mice did not express GA1 and had total brain ganglioside and GM1 concentrations similar to those in the d−/+ and +/+ mice. These results suggest that the reduced brain β-gal activity alone cannot account for the elevation of total brain gangliosides and GM1 in the D2 mice.