Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Charcot-Marie-Tooth (CMT) disease is the most-common form of inherited motor and sensory neuropathy. The autosomal dominant axonal form of the disease (CMT2) is currently subdivided into seven types based on genetic localization. These are CMT2A (1p35-p36), CMT2B (3q13-q22), CMT2C (unknown), CMT2D (7p14), CMT2E (8p21), HMNSP (3q13.1), and CMT2F (7q11-q21). Two loci have thus far been identified for autosomal recessive CMT2; ARCMT2A (1q21.1-q21.3) and ARCMT2B (19q13.3). Mutations in four genes (connexin 32, myelin protein zero, neurofilament-light, and kinesin) have been associated with the CMT2 phenotype. We identified a novel neurofilament-light missense mutation (C64T) that causes the disease in a large Slovenian CMT2 family. This novel mutation shows complete co-segregation with the dominantly inherited CMT2 phenotype in our family.
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PMID:A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family. 1248 88

How membrane biosynthesis and homeostasis is achieved in myelinating glia is mostly unknown. We previously reported that loss of myotubularin-related protein 2 (MTMR2) provokes autosomal recessive demyelinating Charcot-Marie-Tooth type 4B1 neuropathy, characterized by excessive redundant myelin, also known as myelin outfoldings. We generated a Mtmr2-null mouse that models the human neuropathy. We also found that, in Schwann cells, Mtmr2 interacts with Discs large 1 (Dlg1), a scaffold involved in polarized trafficking and membrane addition, whose localization in Mtmr2-null nerves is altered. We here report that, in Schwann cells, Dlg1 also interacts with kinesin 13B (kif13B) and Sec8, which are involved in vesicle transport and membrane tethering in polarized cells, respectively. Taking advantage of the Mtmr2-null mouse as a model of impaired membrane formation, we provide here the first evidence for a machinery that titrates membrane formation during myelination. We established Schwann cell/DRG neuron cocultures from Mtmr2-null mice, in which myelin outfoldings were reproduced and almost completely rescued by Mtmr2 replacement. By exploiting this in vitro model, we propose a mechanism whereby kif13B kinesin transports Dlg1 to sites of membrane remodeling where it coordinates a homeostatic control of myelination. The interaction of Dlg1 with the Sec8 exocyst component promotes membrane addition, whereas with Mtmr2, negatively regulates membrane formation. Myelin outfoldings thus arise as a consequence of the loss of negative control on the amount of membrane, which is produced during myelination.
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PMID:Dlg1, Sec8, and Mtmr2 regulate membrane homeostasis in Schwann cell myelination. 1958 93

Kinesin-1 is a motor protein that moves stepwise along microtubules by employing dimerized kinesin heavy chain (Khc) subunits that alternate cycles of microtubule binding, conformational change, and ATP hydrolysis. Mutations in the Drosophila Khc gene are known to cause distal paralysis and lethality preceded by the occurrence of dystrophic axon terminals, reduced axonal transport, organelle-filled axonal swellings, and impaired action potential propagation. Mutations in the equivalent human gene, Kif5A, result in similar problems that cause hereditary spastic paraplegia (HSP) and Charcot-Marie-Tooth type 2 (CMT2) distal neuropathies. By comparing the phenotypes and the complementation behaviors of a large set of Khc missense alleles, including one that is identical to a human Kif5A HSP allele, we identified three routes to suppression of Khc phenotypes: nutrient restriction, genetic background manipulation, and a remarkable intramolecular complementation between mutations known or likely to cause reciprocal changes in the rate of microtubule-stimulated ADP release by kinesin-1. Our results reveal the value of large-scale complementation analysis for gaining insight into protein structure-function relationships in vivo and point to possible paths for suppressing symptoms of HSP and related distal neuropathies.
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PMID:Three routes to suppression of the neurodegenerative phenotypes caused by kinesin heavy chain mutations. 2271 10

Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot-Marie-Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs.
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PMID:Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments. 2372 42

SPG10 is an autosomal dominant hereditary spastic paraplegia (HSP) caused by mutations in the gene KIF5A encoding the heavy chain of kinesin, a motor protein implied in motility functions within cells. Most of the KIF5A mutations are clustered in 2 areas of motor domain of the protein, the switch regions I and II, that are necessary for microtubules interaction. The set of mutations in KIF5A described so far account for a spectrum of clinical heterogeneity ranging from pure HSP to isolated peripheral nerve involvement (Charcot-Marie-Tooth phenotype) or complicated HSP phenotypes. We here describe a patient presenting with progressive walking difficulties and burning dysesthesias, numbness, and pain at distal segments of the 4 limbs. Neurological examination revealed severe spastic gait and vibratory and proprioception sensory reduction in the lower limbs. Motor and sensory nerve conduction studies disclosed axonal damage of peripheral nerves at lower limbs. We identified the novel variant c.967C>T in the KIF5A gene resulting in the R323W change, which is located at the C-terminus of the motor domain of the KIF5A protein, just upstream the linker region but out of the switch regions. Our findings confirm that the "mixed" central-peripheral involvement is the most frequent clinical picture related to KIF5A motor domain mutations and that motor domain "in toto," even outside of the switch regions, is a hot spot for pathogenic mutations. We stress the concept that detection of a peripheral axonal neuropathy in an autosomal dominant HSP patient should be regarded as an important diagnostic tool and should guide clinicians to seek, first of all, KIF5A mutations.
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PMID:A novel mutation in motor domain of KIF5A associated with an HSP/axonal neuropathy phenotype. 2569 20