Evidence of kinesin heavy chain (
            <i>KIF5A</i>
            ) involvement in pure hereditary spastic paraplegia

Fichera, Marco; Giudice, Mariangela Lo; Falco, Michele; Sturnio, Maurizio; Amata, Silvestra; Calabrese, Olga; Bigoni, Stefania; Calzolari, Elisa; Neri, Marcella

doi:10.1212/01.wnl.0000138731.60693.d2

Cited by 107 publications

(63 citation statements)

References 10 publications

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“…It should be emphasized that, in our study, motor deficits were not examined in other transgenic variants. It is not presently known whether these behavioral manifestations are a direct result of impairments in FAT and/or tau pathology, but it is significant that loss-of-function mutations in a single kinesin-1 heavy chain gene (KIF5A) suffice to produce motor neuron degeneration in some forms of hereditary spastic paraplegia (Reid et al, 2002;Fichera et al, 2004). Regardless, we considered the possibility that impaired motor function may result from pathological mechanisms unrelated to impaired FAT, but we did not observe altered myelination in the sciatic nerve, abnormal CMAP, or neurogenic muscular atrophy.…”

Section: Discussionmentioning

confidence: 99%

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Lazarov¹,

Morfini²,

Pigino³

et al. 2007

Journal of Neuroscience

123

109

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Presenilins (PS) play a central role in ␥-secretase-mediated processing of ␤-amyloid precursor protein (APP) and numerous type I transmembrane proteins. Expression of mutant PS1 variants causes familial forms of Alzheimer's disease (FAD). In cultured mammalian cells that express FAD-linked PS1 variants, the intracellular trafficking of several type 1 membrane proteins is altered. We now report that the anterograde fast axonal transport (FAT) of APP and Trk receptors is impaired in the sciatic nerves of transgenic mice expressing two independent FAD-linked PS1 variants. Furthermore, FAD-linked PS1 mice exhibit a significant increase in phosphorylation of the cytoskeletal proteins tau and neurofilaments in the spinal cord. Reductions in FAT and phosphorylation abnormalities correlated with motor neuron functional deficits. Together, our data suggests that defects in anterograde FAT may underlie FAD-linked PS1-mediated neurodegeneration through a mechanism involving impairments in neurotrophin signaling and synaptic dysfunction.

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Section: Discussionmentioning

confidence: 99%

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Lazarov¹,

Morfini²,

Pigino³

et al. 2007

Journal of Neuroscience

123

109

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“…The mitochondrial fission gene is dynamin-like protein (DLP1). Defects have been associated with human disease in the following genes: KIF5A causing hereditary spastic paraplegia (SPG10), OPA1 causing autosomal dominant optic atrophy, MFN2 causing CMT disease type 2A, and Ganglioside-induced differentiation-associated protein 1 (GDAP1) also causing a CMT disease [76][77][78].…”

Section: Defects In Mitochondrial Dynamics: Fission and Fusionmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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“…and H.H. The vast majority of mutations have been identified mainly in the motor domain [1][2][3][4][5][6][7][8][9] ; therefore, this domain was screened in 2 series of patients. The first series included 186 unrelated patients with a clinical diagnosis of HSP with or without neuropathy (HSP series) and the second included 215 unrelated patients with axonal neuropathy consistent with CMT2 (CMT2 series).…”

mentioning

confidence: 99%

Extended phenotypic spectrum of KIF5A mutations

et al. 2014

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Objective: To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2).Methods: KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing.Results: Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features.Conclusion: This is currently the largest study investigating KIF5A mutations. By combining nextgeneration sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2. Neurology ® 2014;83:612-619 GLOSSARY CMT2 5 Charcot-Marie-Tooth disease type 2; HSP 5 hereditary spastic paraplegia; KHC 5 kinesis heavy chain; SPG10 5 spastic paraplegia type 10; WES 5 whole-exome sequencing.

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Evidence of kinesin heavy chain ( KIF5A ) involvement in pure hereditary spastic paraplegia

Cited by 107 publications

References 10 publications

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Impairments in Fast Axonal Transport and Motor Neuron Deficits in Transgenic Mice Expressing Familial Alzheimer's Disease-Linked Mutant Presenilin 1

Mitochondrial Disease in Childhood: Nuclear Encoded

Extended phenotypic spectrum of KIF5A mutations

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