Inheritance of lysosomal acid beta-galactosidase activity and gangliosides in crosses of DBA/2J and knockout mice.
GM1 gangliosidosis is a progressive neurodegenerative disease caused by deficiencies in lysosomal acid beta-galactosidase (beta-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 beta-gal knockout (ko) mice express residual tissue beta-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 beta-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 beta-gal (Bgl) in the D2 and the ko mice were functionally allelic and if the reduced brain beta-gal activity in D2 mice could account for elevations in total brain gangliosides and GM1. Crosses were made between D2 mice homozygous for the Bgld 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 beta-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 beta-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 beta-gal activity alone cannot account for the elevation of total brain gangliosides and GM1 in the D2 mice.
Hauser
Eric C
EC
Department of Biology, Boston College, Chestnut Hill, Massachusetts, USA.
Kasperzyk
Julie L
JL
d'Azzo
Alessandra
A
Seyfried
Thomas N
TN
D000483:Alleles; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003433:Crosses, Genetic; D005260:Female; D005677:G(M1) Ganglioside / Q000378:metabolism; D005732:Gangliosides / Q000235:genetics*; D006579:Heterozygote; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism; D013045:Species Specificity; D013997:Time Factors; D001616:beta-Galactosidase / Q000096:biosynthesis* / Q000235:genetics*
D005732:Gangliosides; D005677:G(M1) Ganglioside; C021502:acid beta-galactosidase; D001616:beta-Galactosidase