Tay-Sachs disease in Jacob sheep

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Progressive neurodegenerative disorders can manifest as neuronal storage diseases.
• Lysosomal enzyme deficiencies are a known cause of such disorders, including Tay-Sachs disease.

Purpose of the Study:

• To investigate the cause of a neurodegenerative disorder in young Jacob sheep.
• To characterize the genetic and biochemical basis of the disease.
• To establish a potential animal model for Tay-Sachs disease research.

Main Methods:

• Autopsy and biochemical analysis of affected sheep brains and livers.
• Lysosomal enzyme assays and cellulose acetate electrophoresis to measure hexosaminidase A (Hex A) activity.
• Cloning, sequencing, and mutation analysis of the sheep hexa cDNA.
• Cell-based assays to assess cross-species protein interactions.
• Restriction site analysis to determine heterozygote frequency.

Main Results:

• Affected sheep exhibited diminished Hex A activity and accumulated G(M2)-ganglioside and asialo-G(M2)-ganglioside.
• A novel missense mutation in the hexa cDNA, causing exon 11 skipping, was identified.
• Sheep Hex α-subunits did not dimerize with human Hex β-subunits.
• The mutation's heterozygote frequency in Jacob sheep was found to be approximately 14%.

Conclusions:

• Jacob sheep possess a naturally occurring animal model of Tay-Sachs disease due to a specific hexa mutation.
• This model exhibits key biochemical and pathological features of the human disease.
• The identified mutation and animal model hold promise for preclinical gene therapy trials.