A startling canine gene discovery – The cause of a neurological disorder determined

A new gene variant was identified in dogs to cause a neurological disorder known as hyperekplexia. It induces exaggerated startle responses to unexpected sounds, contact or other sudden stimuli. The study reveals similarities and differences between species affected by the diseases.

Researchers from the University of Helsinki and the Folkhälsan Research Center, together with their partners, determined the cause of startle disease, or hyperekplexia, a neural disorder occurring in dogs. Triggered by sudden sounds, puppies with the disease have episodes of muscle rigidity. The disease was observed in Miniature Australian Shepherds in Germany. The breed is also registered under the name Miniature American Shepherd. 

A mutation in the GLRA1 gene was found underlying the disease. A protein which the gene produces is an important part of the glycine receptor in the central nervous system, through which the neurotransmitter glycine regulates neurone function between the brain and muscles. Because of the gene defect, neurons are more sensitive to various stimuli, manifesting in patients as exaggerated startle responses and excessive muscle contraction.   

“The discovered variant is very harmful, and likely inhibits the functioning of the entire glycine receptor. In fact, the disease was very severe and rapidly progressing in the dogs studied, and the puppies had to be euthanised before adulthood,” says Marjo Hytönen, Docent in molecular genetics. 

Hyperekplexia is recessively inherited, meaning that the affected puppies have two copies of the gene defect in their genome. The occurrence of the defect was investigated in various datasets pertaining to the same breed and other breeds around the world. The largest dataset included more than 140,000 dogs from a range of breeds around the world. The variant was not found in Finnish Miniature American Shepherds. The screening identified instead several carriers of the disease in German representatives of the breed as well as in American mixed-bred dogs with Miniature American Shepherd in the mix.  

“This leads us to the conclusion that the gene has most likely mutated in the breed’s native population in the United States, from where it h as spread elsewhere.  In any case, this is a rare disease, and hyperekplexia caused by a defect in the GLRA1 gene has not previously been reported in dogs. Now, a gene test enables the easy identification of carriers, making it possible to consider them in breeding,” says Doctoral Researcher Tiina Heinonen, who specialises in genetics. 

Mutations in the GLRA1 gene are known to cause hyperekplexia also in humans, making dogs carrying the disease a natural disease model for humans. 

“The gene finding is significant for the breed and canine health, in addition to which it can help to better understand human hyperekplexia caused by GLRA1 variants. So far, no GLRA1 mutations of such severity have been identified in human patients. This may go some way towards explaining why clonazepam, a drug effectively used in humans, was ineffective in dogs,” says Professor Hannes Lohi from the Faculty of Veterinary Medicine, University of Helsinki.  


Original article: 

Tiina Heinonen,  Thomas Flegel,  Hanna Müller,  Alexandra Kehl, Sruthi Hundi, Kaspar Matiasek, Andrea Fischer, Jonas Donner, Oliver P. Forman, Hannes Lohi*, Marjo K. Hytönen*: A loss of function variant in canine GLRA1 associates with a neurological disorder resembling human hyperekplexia. Human Genetics 2023. 

Tiina Heinonen, tiina.heinonen@helsinki.fi