Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.
Joy Irobi,Katrien Van Impe,Pavel Seeman,Albena Jordanova,Ines Dierick,Nathalie Verpoorten,Andrej Michalik,Els De Vriendt,An Jacobs,Veerle Van Gerwen,Krist'l Vennekens,Radim Mazanec,Ivailo Tournev,David Hilton-Jones,Kevin Talbot,Ivo Kremensky,Ludo Van Den Bosch,Wim Robberecht,Joël Vandekerckhove,Christine Van Broeckhoven,Jan Gettemans,Peter De Jonghe,Vincent Timmerman +22 more
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TLDR
The same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8) is identified in two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, providing further evidence that mutations in heat- shock proteins have an important role in neurodegenerative disorders.Abstract:
Distal hereditary motor neuropathies are pure motor disorders of the peripheral nervous system resulting in severe atrophy and wasting of distal limb muscles. In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). We found a second mutation (K141E) in two smaller families. Both mutations target the same amino acid, which is essential to the structural and functional integrity of the small heat-shock protein alphaA-crystallin. This positively charged residue, when mutated in other small heat-shock proteins, results in various human disorders. Coimmunoprecipitation experiments showed greater binding of both HSPB8 mutants to the interacting partner HSPB1. Expression of mutant HSPB8 in cultured cells promoted formation of intracellular aggregates. Our findings provide further evidence that mutations in heat-shock proteins have an important role in neurodegenerative disorders.read more
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Modulation of neurodegeneration by molecular chaperones.
TL;DR: It is proposed that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades.
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Role of Axonal Transport in Neurodegenerative Diseases
TL;DR: The role of axonal transport in neurodegenerative disease is reviewed and disruption of axon transport is an early and perhaps causative event in many of these diseases.
Journal ArticleDOI
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy
Oleg V. Evgrafov,Irena Mersiyanova,Joy Irobi,Ludo Van Den Bosch,Ines Dierick,Conrad L. Leung,Olga Schagina,Nathalie Verpoorten,Katrien Van Impe,V P Fedotov,Elena L. Dadali,Michaela Auer-Grumbach,Christian Windpassinger,Klaus Wagner,Zoran Mitrović,David Hilton-Jones,Kevin Talbot,Jean-Jacques Martin,Natalia Vasserman,Svetlana Tverskaya,A. V. Polyakov,Ronald K.H. Liem,Jan Gettemans,Wim Robberecht,Peter De Jonghe,Vincent Timmerman +25 more
TL;DR: A missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F is reported and four additional missense mutations are identified.
Journal ArticleDOI
ATP7A-related copper transport diseases-emerging concepts and future trends
TL;DR: It is indicated that ATP7A has a crucial but previously unappreciated role in motor neuron maintenance, and that the mechanism underlying ATP 7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology.
Journal ArticleDOI
Three-dimensional reconstruction of protein networks provides insight into human genetic disease.
TL;DR: It is found that in-frame mutations are enriched on the interaction interfaces of proteins associated with the corresponding disorders, and that the disease specificity for different mutations of the same gene can be explained by their location within an interface.
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Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V
Anthony Antonellis,Anthony Antonellis,Rachel E. Ellsworth,Nyamkhishig Sambuughin,Imke Puls,Annette Abel,Shih Queen Lee-Lin,Albena Jordanova,Ivo Kremensky,Kyproula Christodoulou,Lefkos T. Middleton,Kumaraswamy Sivakumar,Victor Ionasescu,Benoît Funalot,Jeffery M. Vance,Lev G. Goldfarb,Kenneth H. Fischbeck,Eric D. Green +17 more
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