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

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.

A 63-bp insertion in exon 2 of the porcineKIF21Agene is associated with arthrogryposis multiplex congenita

“…We did not detect the 63-bp insertion in KIF21A in the homozygous state, suggesting that it represents a lethal allele. Furthermore, mutations in kinesin superfamily proteins (KIFs) cause spasticity of limbs (Reid et al 2002, Dor et al 2014, Duchesne et al 2018, supporting our findings that a loss-of-function allele in porcine KIF21A gene is associated with AMC.…”

KIF1C Variants Are Associated with Hypomyelination, Ataxia, Tremor, and Dystonia in Fraternal Twins

“…Authors hypothesized that KIF1C loss of function alters membrane trafficking and membrane wrapping in oligodendrocytes along axons, highlighting the role of KIF1C protein in preserving the structural integrity and function of myelin. 19 The observation of a hypomyelinating leukoencephalopathy in our patients, supporting the early involvement of oligodendrocytes in the disease process, is of particular relevance in this context.…”

“…18 Instead, a KIF1C -mutated cattle has been proposed as the first efficient animal model to explore KIF1C function. 19 KIF1C-deficient cattle display a progressive form of ataxia named ataxia of Charolais, mimicking spastic ataxia in humans. Authors hypothesized that KIF1C loss of function alters membrane trafficking and membrane wrapping in oligodendrocytes along axons, highlighting the role of KIF1C protein in preserving the structural integrity and function of myelin.…”

Frameshift Variant in Novel Adenosine-A1-Receptor Homolog Associated With Bovine Spastic Syndrome/Late-Onset Bovine Spastic Paresis in Holstein Sires

“…In one BSS case report, demyelination was detected, which was later interpreted as a link to multiple sclerosis (Wells et al, 1987;Goeckmann et al, 2018). However, similar lesions were later identified also in Charolais cattle with progressive ataxia and American Brown Swiss with spinal demyelination (Thomsen et al, 2010;Duchesne et al, 2018). Spinal demyelination is caused by SPAST and was already mentioned for HSP4 before (Shoukier et al, 2009).…”