title: Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Arimura
authors.forename: Takeharu
authors.initials: T
authors.lastname: Hayashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shibata
authors.forename: Shitoshi
authors.initials: S
authors.lastname: Hiroi
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Natsuko
authors.initials: N
authors.lastname: Inagaki
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hinohara
authors.forename: Megumi
authors.initials: M
authors.lastname: Takahashi
authors.forename: Satoh-Itoh
authors.initials: SI
authors.lastname: Manatsu
authors.forename: Taishi
authors.initials: T
authors.lastname: Sasaoka
authors.forename: Toru
authors.initials: T
authors.lastname: Izumi
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
authors.forename: Ketty
authors.initials: K
authors.lastname: Schwartz
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
mesh_terms: 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
chemical_list: C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors