title: Tay-Sachs disease in Jacob sheep.
abstract: Autopsy studies of four Jacob sheep dying within their first 6-8 months of a progressive neurodegenerative disorder suggested the presence of a neuronal storage disease. Lysosomal enzyme studies of brain and liver from an affected animal revealed diminished activity of hexosaminidase A (Hex A) measured with an artificial substrate specific for this component of β-hexosaminidase. Absence of Hex A activity was confirmed by cellulose acetate electrophoresis. Brain lipid analyses demonstrated the presence of increased concentrations of G(M2)-ganglioside and asialo-G(M2)-ganglioside. The hexa cDNA of Jacob sheep was cloned and sequenced revealing an identical number of nucleotides and exons as in human HexA and 86% homology in nucleotide sequence. A missense mutation was found in the hexa cDNA of the affected sheep caused by a single nucleotide change at the end of exon 11 resulting in skipping of exon 11. Transfection of normal sheep hexa cDNA into COS1 cells and human Hex A-deficient cells led to expression of Hex S but no increase in Hex A indicating absence of cross-species dimerization of sheep Hex α-subunit with human Hex β-subunits. Using restriction site analysis, the heterozygote frequency of this mutation in Jacob sheep was determined in three geographically separate flocks to average 14%. This large naturally occurring animal model of Tay-Sachs disease is the first to offer promise as a means for trials of gene therapy applicable to human infants.
authors.affiliation: Department of Neurology, New York University School of Medicine, NY, USA.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Torres
authors.forename: Bai Jin
authors.initials: BJ
authors.lastname: Zeng
authors.forename: Brian F
authors.initials: BF
authors.lastname: Porter
authors.forename: Joseph
authors.initials: J
authors.lastname: Alroy
authors.forename: Fred
authors.initials: F
authors.lastname: Horak
authors.forename: Joan
authors.initials: J
authors.lastname: Horak
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Kolodny
mesh_terms: D000818:Animals; D001483:Base Sequence; D001923:Brain Chemistry; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005678:G(M2) Ganglioside / Q000378:metabolism; D006579:Heterozygote; D054818:Hexosaminidase A / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D017354:Point Mutation; D012689:Sequence Homology, Nucleic Acid; D012756:Sheep; D012757:Sheep Diseases / Q000201:enzymology / Q000235:genetics*; D013661:Tay-Sachs Disease / Q000201:enzymology / Q000235:genetics / Q000662:veterinary*; D014162:Transfection; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D005678:G(M2) Ganglioside; D054818:Hexosaminidase A; D001619:beta-N-Acetylhexosaminidases; D019158:N-Acetylneuraminic Acid