Ataxia, spinocerebellar, RALGAPA1- related

 

Gene: RALGAPA1

Transmission: Autosomal, recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Deletion, RALPAGA1 gene: 4.8 kb deletion removing exon35, p.(Val2027Gln frameshift STOP 7), chromosome 8.

Breed: Belgian Shepherd Dog (Malinois type)

Medical system: Neurological

Age of onset of symptoms: By 4 weeks of age.

Ataxia is the clinical description of uncoordinated voluntary movements, resulting from cerebellar and/or brain stem lesions that can be physical or genetic (hereditary) in nature.  Belgian Shepherd puppies of the Malinois type from two separate litters were diagnosed at four weeks of age with ataxia, exaggerated movements and intention tremor.  These clinical signs stabilized but remained present in adulthood.  Several puppies were euthanized due to clinical signs and their bodies submitted to necropsy.  Macroscopically the nervous system appeared normal, while histological examination of the cerebellum revealed abnormal deposits within Purkinje cells.  DNA studies of the affected animals detected a homozygous 4.8 kb deletion in the RALPAGA1 gene that removed exon35 and would result in a premature stop.  The RALPAGA1 gene codes for a protein involved in numerous cellular processes including cell migration and neuron polarity.  It is important for normal brain development, and human patients with RALPAGA1 mutations have neuromuscular disabilities.  Testing of 827 normal Belgian Shepherd dogs for the PALPAGA1 mutation revealed a carrier frequency of 5.1%, while the mutation was not seen in 929 control genomes representing other breeds.

Veterinarians and breeders of Belgian Shepherd dogs should now use DNA testing and selective breeding to reduce and eventually eliminate the PALPAGA1 mutation and the resulting disease from this breed.

Several cerebellar ataxias have now been reported and characterized at the molecular level in the Belgian Shepherd dog breed, including:

KCNJ10 gene. OMIA link [2089-9615]

ATP1B2 gene. OMIA link [2110-9615]

SELENOP gene. OMIA link [2367-9615]

SLC12A6 gene. OMIA link [2279-9615]

RALPAGA1 gene.  OMIA link [2757-9615]

 

References:

OMIA link: [2757-9615]

Christen M, Zdora I, Leschnik M, et al. (2023) RALGAPA1 deletion in Belgian shepherd dogs with cerebellar ataxia. Genes (Basel) 14:1520. [pm/37628572]

Cocostîrc V, Paștiu AI, Pusta DL. (2023) An overview of canine inherited neurological disorders with known causal variants. Animals (Basel) 13:3568. [pm/38003185]

Stee K, Van Poucke M, Lowrie M, et al. (2023) Phenotypic and genetic aspects of hereditary ataxia in dogs. J Vet Intern Med 37:1306-1322. [pm/37341581]

 

Contributed by: Maude Boisvert and Sarah-Maude Paquin, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)