Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a cardiac disease characterized by dilated ventricle and systolic dysfunction. Most of the DCM patients are sporadic cases, but a certain population of DCM patients can be familial cases caused by mutations in genes for sarcomere/Z-disc components including titin/connectin. However, disease-causing mutations could be identified only in a part of the familial DCM patients, suggesting that there should be other disease causing genes for DCM. To explore a novel disease gene for DCM, we searched for mutations in FHL2, encoding for four and half LIM protein 2 (FHL2) in DCM patients, because FHL2 is known to associate with titin/connectin. A missense mutation, Gly48Ser, was identified in a patient with familial DCM. Functional analysis demonstrated that the FHL2 mutation affected the binding to titin/connectin. Because FHL2 protein is known to tether metabolic enzymes to titin/connectin, these observations suggest that the Gly48Ser mutation may be involved in the pathogenesis of DCM via impaired recruitment of metabolic enzymes to the sarcomere.
Arimura
Takuro
T
Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
Hayashi
Takeharu
T
Matsumoto
Yuji
Y
Shibata
Hiroki
H
Hiroi
Shitoshi
S
Nakamura
Takeyuki
T
Inagaki
Natsuko
N
Hinohara
Kunihiko
K
Takahashi
Megumi
M
Manatsu
Satoh-Itoh
SI
Sasaoka
Taishi
T
Izumi
Toru
T
Bonne
Gisèle
G
Schwartz
Ketty
K
Kimura
Akinori
A
D000595:Amino Acid Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors