Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across life span

Yücel‐Yılmaz, Didem; Yücesan, Emrah; Yalnızoğlu, Dilek; Oğuz, Kader K.; Sağıroğlu, Mahmut Şamil; Özbek, Uğur; Serdaroǧlu, Esra; Bılgıç, Başar; Erdem, Sevim; İşeri, Sibel Aylin Uğur; Hanağası, Haşmet; Gürvit, Hakan; Özgül, Rıza Köksal; Dursun, Ali

doi:10.1016/j.braindev.2018.02.013

Cited by 14 publications

(17 citation statements)

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“…KIF1C human gene mutations, including nonsense, missense, splicing or frame shift types, were mainly localized in the kinesin motor domain [ 11 , 13 , 32 ], but coiled-coil, PTDP1 and FHA domains were also affected by deletion or missense mutations [ 11 – 13 ] ( S6 Fig ). The majority of the known mutations, localized in the microtubule-based motor domain disturb adenosine triphosphate hydrolysis of the microtubule.…”

Section: Discussionmentioning

confidence: 99%

“…The first clinical signs observed in KIF1C mutated bovine were often an ataxic gait associated with weakness of the hind limbs, reminiscent of spasticity, which progressed slowly to the typical phenotype of spastic ataxia and ultimately led to recumbency. In humans, KIF1C mutations account for spastic ataxia SPAX2 or complex hereditary spastic paraplegia SPG58 [ 10 – 13 ]. The phenotype in patients is heterogeneous, associating spasticity and in some instance ataxia, thus resembling to the phenotype observed in cattle [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“… Adapted from [ 11 ]. Mutations of human KIF1C resulting in hereditary spastic paraplegia cases are presented: mutations published by [ 11 ] are written in grey, mutations published by [ 32 ] are written in blue, mutations published by [ 12 ]are written in green, mutations published by [ 13 ] are written in black. Mutation of bovine KIF1C resulting in progressive ataxia is presented in red.…”

Section: Supporting Informationmentioning

confidence: 99%

“…Mutations of genes encoding motor proteins, such as kinesin superfamily proteins (KIFs), have been implicated in various HSP clinical isoforms. KIF5A mutations account for autosomal dominant spastic paraplegia (SPG) 10 [ 5 – 7 ], mutations in KIF1A lead to autosomal recessive SPG30 or to autosomal dominant cases of complex HSP [ 8 , 9 ] and mutations in KIF1C have been found in autosomal recessive SPG58/SPAX2 [ 10 – 13 ]. Seven unrelated HSP families from the Middle East, Turkey, North Africa and Germany have been shown to segregate with either non-sense mutations, missense mutations or deletions in KIF1C gene.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Supporting Informationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

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“…KIF1C (Kinesin Family Member 1C MIM 603060) variants have been associated with hereditary spastic paraplegia (HSP) and spastic ataxia-2 (SPAX2 MIM 611302). 1–4 Patients bearing KIF1C variants were first reported in two consanguineous Palestinian and Moroccan families with early-onset cerebellar ataxia followed by pyramidal symptoms, 1 at a locus previously associated with autosomal recessive spastic ataxia-2 (SPAX2 MIM 611302). 5 Subsequently, Novarino et al identified a homozygous deletion of exon 14–18 in the original SPAX2 family, confirming that KIF1C was the SPAX2 gene.…”

Section: Introductionmentioning

confidence: 99%

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

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Keren

et al. 2019

Tremor and Other Hyperkinetic Movements

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Background: KIF1C (Kinesin Family Member 1C) variants have been associated with hereditary spastic paraplegia and spastic ataxia. Case report: We report fraternal twins presenting with cerebellar ataxia and dystonic tremor. Their brain MRI showed a hypomyelinating leukoencephalopathy. Whole exome sequencing identified a homozygous KIF1C variant in both patients. Discussion: KIF1C variants can manifest as a complex movement disorder with cerebellar ataxia and dystonic tremor. KIF1C variants may also cause a hypomyelinating leukoencephalopathy.

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The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

et al. 2019

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There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders. The work of this task force was based on a previously published systematic scoping review of the literature that identified autosomal recessive disorders characterized primarily by cerebellar motor dysfunction and cerebellar degeneration. The task force regrouped 12 international ataxia experts who decided on general orientation and specific issues. We identified 59 disorders that are classified as primary autosomal recessive cerebellar ataxias. For each of these disorders, we present geographical and ethnical specificities along with distinctive clinical and imagery features. These primary recessive ataxias were organized in a clinical and a pathophysiological classification, and we present a general clinical approach to the patient presenting with ataxia. We also identified a list of 48 complex multisystem disorders that are associated with ataxia and should be included in the differential diagnosis of autosomal recessive ataxias. This classification is the result of a consensus among a panel of international experts, and it promotes a unified understanding of autosomal recessive cerebellar disorders for clinicians and researchers.

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Clinical phenotype of hereditary spastic paraplegia due to KIF1C gene mutations across life span

Cited by 14 publications

References 13 publications

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

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

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

The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

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