title: Phenotype of cardiomyopathy in cardiac-specific heat shock protein B8 K141N transgenic mouse.
abstract: A K141N missense mutation in heat shock protein (HSP) B8, which belongs to the small HSP family, causes distal hereditary motor neuropathy, which is characterized by the formation of inclusion bodies in cells. Although the HSPB8 gene causes hereditary motor neuropathy, obvious expression of HSPB8 is also observed in other tissues, such as the heart. The effects of a single mutation in HSPB8 upon the heart were analyzed using rat neonatal cardiomyocytes. Expression of HSPB8 K141N by adenoviral infection resulted in increased HSPB8-positive aggregates around nuclei, whereas no aggregates were observed in myocytes expressing wild-type HSPB8. HSPB8-positive aggresomes contained amyloid oligomer intermediates that were detected by a specific anti-oligomer antibody (A11). Expression of HSPB8 K141N induced slight cellular toxicity. Recombinant HSPB8 K141N protein showed reactivity against the anti-oligomer antibody, and reactivity of the mutant HSPB8 protein was much higher than that of wild-type HSPB8 protein. To extend our in vitro study, cardiac-specific HSPB8 K141N transgenic (TG) mice were generated. Echocardiography revealed that the HSPB8 K141N TG mice exhibited mild hypertrophy and apical fibrosis as well as slightly reduced cardiac function, although no phenotype was detected in wild-type HSPB8 TG mice. A single point mutation of HSPB8, such as K141N, can cause cardiac disease.
authors: Department of Pharmacotherapeutics, School of Pharmacy, Iwate Medical University, Iwate, 028-3694, Japan. asanbe@iwate-med.ac.jp
authors: Atsushi
authors: A
authors: Sanbe
authors: Tetsuro
authors: T
authors: Marunouchi
authors: Tsutomu
authors: T
authors: Abe
authors: Yu
authors: Y
authors: Tezuka
authors: Mizuki
authors: M
authors: Okada
authors: Sayuri
authors: S
authors: Aoki
authors: Hideki
authors: H
authors: Tsumura
authors: Junji
authors: J
authors: Yamauchi
authors: Kouichi
authors: K
authors: Tanonaka
authors: Hideo
authors: H
authors: Nishigori
authors: Akito
authors: A
authors: Tanoue
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D050886:HSP20 Heat-Shock Proteins / Q000235:genetics* / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D050886:HSP20 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C490206:Hspb8 protein, mouse; D018832:Molecular Chaperones; D009124:Muscle Proteins; D011994:Recombinant Proteins
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