Neuroaxonal dystrophy (NAD), RNF170-related

 

Gene: RNF170

Transmission: Autosomal, recessive (likely)

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, RNF170 gene; c.367delG, p.(Ala123Gln frameshift STOP 111), exon1, chromosome 16.

Breed: Miniature American Shepherd

Medical system: Neurological

Age of onset of symptoms: By 2 years.

Neuroaxonal dystrophy (NAD) is a family of neurodegenerative genetic diseases characterized clinically by neurological signs and histologically by the presence of swollen axons in the central nervous system.  A cohort of Miniature American Shepherd dogs were diagnosed with signs of NAD including hind limb weakness, ataxia, abnormal gait and dragging of digits.  These signs were observed in the young adult animal and very slowly progressed over time.  No pain nor balance problems were observed.  Histological examination of necropsy samples showed swollen axons, dilated myelin sheaths and degeneration of neurons, particularly within the brainstem.  DNA studies identified a homozygous mutation in the RNF170 gene as responsible for the clinical observations.  The RNF170 gene encodes a protein involved with the ubiquitin degradation system that is linked to the control of calcium levels within the cell.

In a survey of 485 Miniature American Shepherd dogs including both North American and European animals, a 20% carrier frequency for the mutation in the RNF170 gene was observed. A survey of 320 Australian Shepherds failed to identify the mutation, suggesting that the mutation arose within the Miniature American Shepherd breed after its divergence from the Australian Shepherd breed in the 1960s.  Veterinarians and breeders of the Miniature American Shepherd should now use DNA testing and selective breeding to reduce and eventually eliminate this disease and the mutation within this breed.

Note that Neuroaxonal Dystrophies (NADs) of differing severities and age of onset are seen in different breeds and are caused by mutations in different genes.  Here is a summary:

NAD, Giant Schnauzer type.  A severe disease that is lethal at birth.  MFN2 gene, OMIA [2153].

<astyle=”color: #3c56b5;” href=”https://labgenvet.ca/en/disease/nad-neuroaxonal-dystrophy-papillon-type/”>NAD, Papillon type: A progressive neurological disease with onset of symptoms by 3-4 months and death by 7-8 months.  PLA2G6 gene, OMIA [2105]

NAD, Rottweiler type.  A slowly progressive degenerative disease with a young adult onset usually resulting in ethical euthanasia.  VPS11 gene, OMIA [2152].

NAD, Spanish Water Dog type. A progressive degenerative disease with an onset of 6-11 months and ethical euthanasia by 2 years. TECPR2 gene, OMIA [1975]

NAD, Miniature American Shepherd type.  RNF170 gene.  OMIA [2876]

 

References:

OMIA link: [2876-9615]

Cook SR, Schwarz C, Guevar J, et al. (2024) Canine RNF170 single base deletion in a naturally occurring model for human neuroaxonal dystrophy. Mov Disord 39:2049-2057. [pm/39177409]

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

 

Contributed by: Tatiana Gallien and Laurence Sader, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)