Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy.
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.
Irobi
Joy
J
Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerpen, Belgium.
Van Impe
Katrien
K
Seeman
Pavel
P
Jordanova
Albena
A
Dierick
Ines
I
Verpoorten
Nathalie
N
Michalik
Andrej
A
De Vriendt
Els
E
Jacobs
An
A
Van Gerwen
Veerle
V
Vennekens
Krist'l
K
Mazanec
Radim
R
Tournev
Ivailo
I
Hilton-Jones
David
D
Talbot
Kevin
K
Kremensky
Ivo
I
Van Den Bosch
Ludo
L
Robberecht
Wim
W
Van Vandekerckhove
Joël
J
Van Broeckhoven
Christine
C
Gettemans
Jan
J
De Jonghe
Peter
P
Timmerman
Vincent
V
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
C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases