Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis

Bhagyalaxmi Mohapatra, Shinawe Jimenez, Jiuann Huey Lin, Karla R. Bowles, Karen J. Coveler, Joseph G. Marx, Michele A. Chrisco, Ross T. Murphy, Paul R. Lurie, Robert J. Schwartz, Perry M. Elliott, Matteo Vatta, William McKenna, Jeffrey Towbin, Neil E. Bowles

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Abstract

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and α-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and α-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in α-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and α-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in α-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit α-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.

Original languageEnglish (US)
Pages (from-to)207-215
Number of pages9
JournalMolecular Genetics and Metabolism
Volume80
Issue number1-2
DOIs
StatePublished - Jan 1 2003

Fingerprint

Endocardial Fibroelastosis
Actinin
Dilated Cardiomyopathy
Genes
Mutation
Zyxin
Dystrophin
cysteine and glycine-rich protein 3
Sarcomeres
Muscle Development
Hypertrophic Cardiomyopathy
Cell culture
Lysine
Cysteine
Arginine
Actins
Cultured Cells
Cells
Heart Failure
Cell Culture Techniques

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Mohapatra, B., Jimenez, S., Lin, J. H., Bowles, K. R., Coveler, K. J., Marx, J. G., ... Bowles, N. E. (2003). Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Molecular Genetics and Metabolism, 80(1-2), 207-215. https://doi.org/10.1016/S1096-7192(03)00142-2

Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. / Mohapatra, Bhagyalaxmi; Jimenez, Shinawe; Lin, Jiuann Huey; Bowles, Karla R.; Coveler, Karen J.; Marx, Joseph G.; Chrisco, Michele A.; Murphy, Ross T.; Lurie, Paul R.; Schwartz, Robert J.; Elliott, Perry M.; Vatta, Matteo; McKenna, William; Towbin, Jeffrey; Bowles, Neil E.

In: Molecular Genetics and Metabolism, Vol. 80, No. 1-2, 01.01.2003, p. 207-215.

Research output: Contribution to journalArticle

Mohapatra, B, Jimenez, S, Lin, JH, Bowles, KR, Coveler, KJ, Marx, JG, Chrisco, MA, Murphy, RT, Lurie, PR, Schwartz, RJ, Elliott, PM, Vatta, M, McKenna, W, Towbin, J & Bowles, NE 2003, 'Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis', Molecular Genetics and Metabolism, vol. 80, no. 1-2, pp. 207-215. https://doi.org/10.1016/S1096-7192(03)00142-2
Mohapatra, Bhagyalaxmi ; Jimenez, Shinawe ; Lin, Jiuann Huey ; Bowles, Karla R. ; Coveler, Karen J. ; Marx, Joseph G. ; Chrisco, Michele A. ; Murphy, Ross T. ; Lurie, Paul R. ; Schwartz, Robert J. ; Elliott, Perry M. ; Vatta, Matteo ; McKenna, William ; Towbin, Jeffrey ; Bowles, Neil E. / Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. In: Molecular Genetics and Metabolism. 2003 ; Vol. 80, No. 1-2. pp. 207-215.
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abstract = "Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and α-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and α-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in α-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and α-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in α-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit α-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.",
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T1 - Mutations in the muscle LIM protein and α-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis

AU - Mohapatra, Bhagyalaxmi

AU - Jimenez, Shinawe

AU - Lin, Jiuann Huey

AU - Bowles, Karla R.

AU - Coveler, Karen J.

AU - Marx, Joseph G.

AU - Chrisco, Michele A.

AU - Murphy, Ross T.

AU - Lurie, Paul R.

AU - Schwartz, Robert J.

AU - Elliott, Perry M.

AU - Vatta, Matteo

AU - McKenna, William

AU - Towbin, Jeffrey

AU - Bowles, Neil E.

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N2 - Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and α-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and α-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in α-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and α-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in α-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit α-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.

AB - Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), while mutations in multiple genes cause autosomal dominant DCM. Muscle LIM protein (MLP) is a member of the cysteine-rich protein (CRP) family and has been implicated in both myogenesis and sarcomere assembly. In the latter role, it binds zyxin and α-actinin, both of which are involved in actin organization. An MLP-deficient mouse has been described; these mice develop dilated cardiomyopathy and heart failure. Based upon these data, and the recent descriptions of mutations in MLP in patients with DCM or hypertrophic cardiomyopathy, we screened patients for mutations in the MLP and α-actinin-2 genes. We identified a patient with DCM and EFE, having a mutation in MLP with the residue lysine 69 substituted by arginine (K69R). This is within a highly conserved region adjacent to the first LIM domain involved in α-actinin binding. Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and α-actinin-2 and the cellular localization of MLP was altered. In another individual with DCM, a W4R mutation was identified. However, this mutation did not segregate with disease in this family. In another patient with DCM, a Q9R mutation was identified in α-actinin-2. This mutation also disrupted the interaction with MLP and appeared to inhibit α-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation.

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