title: Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.
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.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Impe
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Ines
authors.initials: I
authors.lastname: Dierick
authors.forename: Nathalie
authors.initials: N
authors.lastname: Verpoorten
authors.forename: Andrej
authors.initials: A
authors.lastname: Michalik
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: An
authors.initials: A
authors.lastname: Jacobs
authors.forename: Veerle
authors.initials: V
authors.lastname: Van Gerwen
authors.forename: Krist'l
authors.initials: K
authors.lastname: Vennekens
authors.forename: Radim
authors.initials: R
authors.lastname: Mazanec
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: David
authors.initials: D
authors.lastname: Hilton-Jones
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Joël
authors.initials: J
authors.lastname: Van Vandekerckhove
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Jan
authors.initials: J
authors.lastname: Gettemans
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases