Alpha B-crystallin mutation in dilated cardiomyopathy.
Mutations in genes for sarcomeric proteins such as titin/connectin are known to cause dilated cardiomyopathy (DCM). However, disease-causing mutations can be identified only in a small proportion of the patients even in the familial cases, suggesting that there remains yet unidentified disease-causing gene(s) for DCM. To explore the novel disease gene for DCM, we examined CRYAB encoding alphaB-crystallin for mutation in the patients with DCM, since alphaB-crystallin was recently reported to associate with the heart-specific N2B domain and adjacent I26/I27 domain of titin/connectin, and we previously reported a N2B mutation, Gln4053ter, in DCM. A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient and the mutation affected the evolutionary conserved amino acid residue among alpha-crystallins. Functional analysis revealed that the mutation decreased the binding to titin/connectin heart-specific N2B domain without affecting distribution of the mutant crystallin protein in cardiomyocytes. In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein. These observations suggest that the Arg157His mutation may be involved in the pathogenesis of DCM via impaired accommodation to the heart-specific N2B domain of titin/connectin and its disease-causing mechanism is different from the mutation found in desmin-related myopathy.
Inagaki
Natsuko
N
Department of Molecular Pathogenesis, Medical Research Institute and Laboratory of Genome Diversity, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Hayashi
Takeharu
T
Arimura
Takuro
T
Koga
Yoshinori
Y
Takahashi
Megumi
M
Shibata
Hiroki
H
Teraoka
Kunihiko
K
Chikamori
Taishiro
T
Yamashina
Akira
A
Kimura
Akinori
A
D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D064211:Connectin; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
C059215:CRYAB protein, human; D064211:Connectin; D009124:Muscle Proteins; C577285:TTN protein, human; D038203:alpha-Crystallin B Chain; D011494:Protein Kinases