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The ataxic bovine model offers the opportunity to better understand the physiopathology of the anomaly. The study of demyelating plaques shows actin aggregats (red) at the middle of these structures and the abnormal proliferation of oligodendrocyte membranes (green).

In1972, a new anomaly was identified in Charolais cattle in different countries: progressive ataxia.

Affected cattle of both sexes deveop incoordination and stiffness of the hind limbs between 12 and 18 months of age. These symptoms worsen in the months that follow, until paralysis of the limbs and death. The first histopathological studies show characteristic lesions exclusively in the central nervous system, mainly affecting white matter. The genetic etiology of the anomaly has long been suspected but not confirmed.

In France, the creation in 2002 of the National Observatory for Bovine Anomalies (ONAB, www.onab.fr) and the active participation of several attentive veterinarians has made it possible to observe the emergence of progressive ataxia.

Genotyping of approximately forty cases with SNP chips validated the exclusively genetic determinism of the anomaly, with an autosomal recessive transmission. The sequencing of the genome of two sick animals allowed the identification of the causal mutation in the gene KIF1C (Kinesin Family member 1C), a non-synonymous substitution in the coding region associated with extinction of the expression of the K1F1C protein in nerve tissues. This mutation seems old: despite good knowledge of pedigrees for over 12 generations no ancestor has been identified as being the one responsible for its spread. Since it is associated with the heterozygous state for an improved muscular and skeletal conformation, it was not eliminated by natural selection. A molecular test is now available and provides a tool of choice for managing this anomaly which is expensive for farms and harmful to animal welfare.

But, beyond its impact on farming, cattle also provide animal models for the study of analogous human pathologies. In man, hereditary spastic paraplegias are clinically and genetically heterogenous human neurodegenerative diseases. The symptoms are a weakness and spasticity of inferior members, a consequence of the degeneration of cortico-spinal axons. Today, more than 70 different genetic types have been described. Mutations of the K1F1C gene are associated with a type 58 hereditary spastic paraplegia (SPG58/SPAX2). For this anomaly, cerebral imaging shows demyelinisation at several locations but the type of cell lesions remain unknown, mainly since it is not possible to sample biological material in patients.

The partnership intitiated between two teams of INRA and the Institut du Cerveau et de la Moelle épinière has shown that ataxic cattle could be considered as the first natural animal model for SPG58, especially since in mice, invalidation of the Kif1c gene does not produce a phenotype. With the bovine model, it is possible to improve our understanding of the physiopathology of the anomaly, notably the cell and molecular nature of the demyelating plaques. Myelin lesions whose diameter rarely exceed 100 micrometers affect several tracts (brain, cerebellum and spinal cord) and are based on the oligodendrocyte. The alteration of K1F1C expression impacts actin transport from the cytoplasma towards the oligodendrocyte coil segments, highlighting the role of kinesins in maintaining the structural and functional integrity of myelin.

In 2017, the test was transferred to three French laboratories, well before publication of the article. It is a tool of choice for managing this anomaly which is both expensive for breeders and harmful to animal welfare. The frenquency of the mutated allele should decrease in the population thanks to selection and in addition, the number of cases should be limited with a breeding policy avoiding risky matings. Like several other known anomalies, this anomaly provides a model for man since no known rodent carries this phentoype. Progressive ataxia of Charolais is therefore a natural animal model for the study of hereditary spastic paraplegia type 58  (SPG58/SPAX2). More generally, it also offers a model for the study of demyelinating disease.