GM2 Gangliosidosis in Shiba Inu Dogs with an In-Frame Deletion in HEXB

Area of Science:

• Veterinary Genetics
• Canine Neurodegenerative Diseases
• Lysosomal Storage Diseases

Background:

• Neuronal ceroid lipofuscinosis (NCL) is a group of progressive neurodegenerative diseases.
• Autofluorescent storage bodies in neurons suggest NCL, but genetic causes can be elusive.

Observation:

• Two related Shiba Inu dogs presented with young-adult onset, progressive neurodegeneration.
• Autofluorescent cytoplasmic storage bodies were observed in neurons.
• Initial genetic analysis for NCL-related variants was negative.

Findings:

• Whole-genome sequencing revealed a homozygous 3 base pair deletion in the HEXB gene in both affected dogs.
• This deletion is analogous to mutations causing Sandhoff disease (GM2 gangliosidosis) in humans.
• GM2 ganglioside accumulation and deficient HEXB enzyme activity were confirmed in affected Shiba Inu brains.

Implications:

• The identified HEXB deletion is the likely cause of the neurodegenerative disease in these Shiba Inu dogs.
• Whole-genome sequencing is a powerful tool for identifying causative genetic variants in canine diseases.
• This discovery aids in understanding canine models of human lysosomal storage diseases.