UC Davis School of Veterinary Medicine Veterinary Genetics Laboratory

Charolais Progressive Ataxia

Introduction

Progressive ataxia (PA) of Charolais cattle is an inherited neurodegenerative disease of the central nervous system. It is caused by abnormal development of the myelin sheath that supports and insulates axons of nerve fibers in specific parts of the brain and spinal cord. PA is characterized by onset of unsteady gait and stiff hind limbs with gradual worsening of the condition that results in an inability to stand and permanent recumbency (lying down). Animals have to be euthanized as there is no effective treatment for this condition. Other signs of the disease include head bobbing when excited and, in females, irregular pulsatile urination. Onset of the disease is typically around 18 months of age but can occur as early as 6 months or as late as 3-5 years. The evolution of the disease is also variable from a few weeks to more than 18 months from onset of signs.

A single base substitution (c.608G>A) in exon 5 of KIF1C gene has been identified as a causal variant  for PA in the Charolais breed. This substitution modifies a conserved amino acid (p.Arg203Gln) resulting in a mutated protein.  In addition, because of the location of this mutation at the end of exon 5, this variant also causes alternative splicing of this gene that skips exon 5 and produces a truncated (shorter) protein. The overall combined effect of the mutation is the absence of KIF1C protein in the brain.

PA is inherited in an autosomal recessive fashion, which means that both males and females are affected and that 2 copies of the defective gene are needed for presentation of the disease. Frequency of PA mutation in the Charolais breed has been recently estimated to be about 13%. In a sample of 3,300 French commercial Charolais cattle screened for the mutation, the incidence of affected animals was around 1.1% among animals aged 7 and just below 1% at 24 months old, with no affected, homozygous animals observed at 30 months of age. The prevalence of the mutation and disease in the Charolais breed result from a popular sire effect tracing to a carrier bull, born in 1964, that had high contribution to the breed, and to a hitch-hiking effect from close proximity of the PA mutation to a genomic region under positive selection for muscular development and weight gain. A very low frequency (less than 0.1%) of the PA mutation has also been found in Blonde d’Aquitaine cattle, which have Charolais influence.

The VGL offers a test for PA in Charolais, Charolais-crossbreds, and Blonde d’Aquitaine cattle. Test results help breeders determine if carriers are present among breeding stock and to use mating strategies to avoid producing affected calves. Carriers can be safely bred to N/N mates as this type of breeding will not produce affected calves. Genetic testing also helps veterinarians to confirm diagnosis of Progressive Ataxia in animals exhibiting signs of the disease. Other neurodegenerative defects occur in Charolais cattle that are not caused by the PA mutation but their ethology is unknown.

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Results are reported as:


N/N

Normal – no copies of the PA mutation are present.

N/PA

Carrier – 1 copy of the PA mutation is present. Animal is normal but can produce affected offspring if bred to another carrier.

PA/PA

Affected – 2 copies of the PA mutation.

Reference:

Duschene A, Vaiman A, Frah M et al. (2018) Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination. PLoS Genet 14(8): e1007550. https://doi.org/10.1371/journal.pgen.1007550

 
Veterinary Genetics Laboratory, Tel 530-752-2211, Email VGL