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

Amandine Duchesne, Anne Vaiman, Magali Frah, Sandrine Floriot, Sabrina Legoueix-Rodriguez, Anne Desmazières, Sébastien Fritz, Christian Beauvallet, Olivier Albaric, Eric Venot, Maud Bertaud, Romain Saintilan, Raphaël Guatteo, Diane Esquerré, Julien Branchu, Anaïs Fleming, Alexis Brice, Frédéric Darios, Jean-Luc Vilotte, Giovanni Stevanin, Didier Boichard, Khalid Hamid El Hachimi
PLoS Genet. 2018-08-01; 14(8): e1007550
DOI: 10.1371/journal.pgen.1007550

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

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

Duchesne A(1), Vaiman A(1), Frah M(2)(3)(4)(5), Floriot S(1), Legoueix-Rodriguez
S(1)(6), Desmazières A(2)(3)(4)(5), Fritz S(1)(7), Beauvallet C(1), Albaric O(8),
Venot E(1), Bertaud M(1), Saintilan R(1)(7), Guatteo R(9), Esquerré D(10),
Branchu J(2)(3)(4)(5), Fleming A(1), Brice A(2)(3)(4)(5)(11), Darios
F(2)(3)(4)(5), Vilotte JL(1), Stevanin G(2)(3)(4)(5)(11)(12), Boichard D(1), El
Hachimi KH(2)(3)(4)(5)(12).

Author information:
(1)GABI, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France.
(2)Sorbonne Université UMR S 1127, Paris, France.
(3)Inserm, U1127, Paris, France.
(4)CNRS, UMR 7225, Paris, France.
(5)Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
(6)TWB, Université de Toulouse, INRA, INSA, CNRS, Ramonville-Saint-Agne, France.
(7)Allice, Paris, France.
(8)LHA, Oniris, Université Nantes Angers Le Mans, Nantes, France.
(9)BIOEPAR, INRA, Oniris, La Chantrerie, Nantes, France.
(10)GenPhySE, Université de Toulouse, INRA, INPT, ENVT, Castanet Tolosan, France.
(11)Centre de référence de Neurogénétique, Fédération de génétique, APHP, GHU
Pitié-Salpêtrière, Paris, France.
(12)EPHE, PSL Research University, Laboratoire de Neurogénétique, Paris, France.

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.

DOI: 10.1371/journal.pgen.1007550
PMCID: PMC6089448
PMID: 30067756 [Indexed for MEDLINE]

Conflict of interest statement: The authors have declared that no competing
interests exist.

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