Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination

PLoS Genet. 2018 Aug 1;14(8):e1007550. doi: 10.1371/journal.pgen.1007550. eCollection 2018 Aug.

Abstract

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous human neurodegenerative diseases. Amongst the identified genetic causes, mutations in genes encoding motor proteins such as kinesins have been involved in various HSP clinical isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2). Bovines also develop neurodegenerative diseases, some of them having a genetic aetiology. Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection for several decades, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock-out, therefore mimicking mutations in humans affected by SPG58/SPAX2. The functional consequences of KIF1C loss of function in cattle were also histologically reevaluated. We showed by an immunochemistry approach that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. We also observed that the lesions were associated with abnormal extension of paranodal sections. Moreover, this model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young-adult Charolais cattle. Finally, this model provides useful information for SPG58/SPAX2 disease and other demyelinating lesions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cattle / genetics*
  • Cattle Diseases / diagnosis
  • Cattle Diseases / genetics*
  • Disease Models, Animal
  • Female
  • Heterozygote
  • Homozygote
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics
  • Intellectual Disability / veterinary
  • Kinesins / genetics
  • Kinesins / metabolism*
  • Male
  • Muscle Spasticity / diagnosis
  • Muscle Spasticity / genetics
  • Muscle Spasticity / veterinary
  • Mutation, Missense
  • Myelin Sheath / metabolism*
  • Optic Atrophy / diagnosis
  • Optic Atrophy / genetics
  • Optic Atrophy / veterinary
  • Polymorphism, Single Nucleotide
  • Spastic Paraplegia, Hereditary / diagnosis
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / veterinary
  • Spinocerebellar Ataxias / diagnosis
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / veterinary
  • Spinocerebellar Degenerations / diagnosis
  • Spinocerebellar Degenerations / genetics
  • Spinocerebellar Degenerations / veterinary*
  • Whole Genome Sequencing

Substances

  • Kinesins

Supplementary concepts

  • Spastic Ataxia

Grant support

This work was supported by the INRA Animal Genetics Department, www.ga.inra.fr (grant to AD), ApisGene (grant to DB) www.apis-gene.com, the French National Research Agency (ANR-14_CE 19-0011 to DB; ANR-13-ISV1-00002 to GS), and the “Investissements d’avenir” programme (grants ANR-10-IAIHU-06 and ANR-11-INBS-0011), www.agence-nationale-recherche.fr and received funding from the Verum Foundation (to AB and GS) www.verum-foundation.com, the Fondation GIS-Maladies Rares (to GS) www.fondation-maladiesrares.org, the Fondation Roger de Spoelberch (to AB)www.fondation-roger-de-spoelberch.ch, the Seventh Framework Programme - FP7 (Omics call to GS) https://ec.europa.eu/research/fp7/index_en.cfm and the E-Rare programme, www.erare.eu (Neurolipid call to GS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.