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

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

doi:10.1016/s1096-7192(03)00142-2

Cited by 241 publications

(175 citation statements)

References 40 publications

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“…As a number of missense mutations in genes encoding for titin and titin-associated proteins have recently been reported to be responsible for DCM, 3,[12][13][14][15][19][20][21][22][23][24][25] we searched in a well-characterized sample of DCM patients for unknown SNPs and/or mutations in the human MYPN and ANKRD1 genes. In order to extend our knowledge on disease-causing mutations in these two proteins expressed in heart tissue, we screened the coding sequences and corresponding intron flanks of the two genes and found two novel non-synonymous mutations in the MYPN gene and only one rare synonymous SNP in the coding region of the ANKRD1 gene.…”

Section: Discussionmentioning

confidence: 99%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

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on behalf of the German Competence Network Heart Failure Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARPencoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the a-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and a-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T4C and c.-79C4T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.

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Section: Discussionmentioning

confidence: 99%

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

et al. 2012

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“…37,38 However, as discussed in the later section, DCM-associated mutations were found in CSRP3 and a-actinin gene (ACTN2), and these mutations decreased binding to each other. 39 Therefore, the decreased binding between MLP and aactinin was associated with both HCM and DCM. This discrepancy should be resolved by further studies.…”

Section: Z-disc Mutations In Hcmmentioning

confidence: 99%

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

Kimura

2010

J Hum Genet

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Cardiomyopathy is caused by functional abnormality of cardiac muscle. The functional abnormality involved in its etiology includes both extrinsic and intrinsic factors, and cardiomyopathy caused by the intrinsic factors is called as idiopathic or primary cardiomyopathy. There are several clinical types of primary cardiomyopathy including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Linkage studies and candidate gene approaches have explored the disease genes for hereditary primary cardiomyopathy. The most notable finding was that mutations in the same disease gene can be found in different clinical types of cardiomyopathy. Functional analyses of disease-related mutations have revealed that characteristic functional alterations are associated with the clinical types, such that increased and decreased Ca 2+ sensitivity due to sarcomere mutations are associated with HCM and DCM, respectively. In addition, our recent studies have suggested that mutations in the Z-disc components found in HCM and DCM may result in increased and decreased stiffness of sarcomere; that is, stiff sarcomere and loose sarcomere, respectively, and hence altered stretch response. More recently, mutations in the components of I region were found in hereditary cardiomyopathy and the functional analyses of the mutations suggested that the altered stress response was associated with cardiomyopathy, further complicating the etiology and pathogenesis. However, elucidation of genetic etiology and functional alterations caused by the mutations shed lights on the new therapeutic approaches to hereditary cardiomyopathy, such that treatment of DCM with a Ca 2+ sensitizer prevented the disease in a mouse model.

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“…Genes underlying IDC have been identified from linkage as well as candidate gene studies, and include those coding for proteins involved in the cytoskeleton (desmin, 5 d-sarcoglycan, 6 dystrophin, 7 desmoplakin 8 and metavinculin 9 ), the Z-disk (muscle LIM protein, 10 a-actinin-2 11 and Cypher/ZASP 12 ), the nuclear envelope (lamin A/C 13 ) and ion conduction (phospholamban, 14 SUR2A 15 and the Na v 1.5 ion channel 16 ). Although genes encoding sarcomeric proteins were traditionally considered to be involved in hypertrophic cardiomyopathy, 17 since 1998 it has also been known that mutations in these genes can cause IDC.…”

Section: Introductionmentioning

confidence: 99%

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

et al. 2009

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We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.

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

Cited by 241 publications

References 40 publications

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy

Molecular basis of hereditary cardiomyopathy: abnormalities in calcium sensitivity, stretch response, stress response and beyond

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

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