Alternative titles; symbols
HGNC Approved Gene Symbol: CSRP3
Cytogenetic location: 11p15.1 Genomic coordinates (GRCh38): 11:19,182,030-19,201,983 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.1 | ?Cardiomyopathy, dilated, 1M | 607482 | 3 | |
| Cardiomyopathy, hypertrophic, 12 | 612124 | Autosomal dominant | 3 |
Weiskirchen et al. (1995) described the CRP family of LIM domain proteins, which includes CRP1 (123876), CRP2 (601871), and CRP3.
Muscle development is a complex, multistep process under the control of both ubiquitous and muscle-specific transcriptional regulators. Arber et al. (1994) described a positive regulator of myogenesis that was cloned from a subtracted cDNA library enriched for messages induced in denervated rat skeletal muscle. The rat cDNA was designated muscle LIM protein (Mlp) because it contains a cysteine-rich domain originally described in the 3 proteins Lin-11, Isl-1 (600366), and Mec-3. Mlp is enriched in striated muscle and its expression coincides with myogenic differentiation. In the absence of Mlp, induced myoblasts express myogenin but fail to exit the cell cycle and differentiate. The rat Mlp cDNA encodes a predicted 194-amino acid protein containing 2 LIM motifs. The protein is highly conserved and Northern blots detected transcripts in chicken and Drosophila, from which the corresponding genes were isolated. The chicken and rat proteins are 93% identical.
Fung et al. (1995) cloned a human cDNA, which they designated cardiac LIM protein (CLP), whose deduced amino acid sequence is 95% identical to that of rat Mlp. The authors proposed that the human gene is the homolog of the rat sequence. Northern blots showed expression in cardiac and slow-twitch skeletal muscles.
Knoll et al. (2002) determined that the CSRP3 gene contains 6 exons and spans a 20-kb genomic region.
Using fluorescence in situ hybridization, Fung et al. (1995) mapped the CSRP3 gene to chromosome 11p15.1.
Knoll et al. (2002) presented biophysical/biochemical studies in Mlp-deficient mouse cardiac muscle that supported a selective role for this Z disc protein in mechanical stretch sensing. They showed that MLP interacts with and colocalizes with telethonin (TCAP; 604488), a titin-interacting protein. Further, a human MLP mutation associated with dilated cardiomyopathy (CMD1M; 607482) resulted in a marked defect in TCAP interaction/localization. Knoll et al. (2002) concluded that the Z disc MLP/TCAP complex is a key component of the in vivo cardiomyocyte stretch sensor machinery and that defects in the complex can lead to human dilated cardiomyopathy and associated heart failure.
Using expression profiling and quantitative RT-PCR, Kostek et al. (2007) found that lengthening exercise followed by shortening exercise resulted in elevated expression of CSRP3 and MUSTN1 (617195) over 24 hours in biopsies of quadriceps muscle of healthy male volunteers.
Geier et al. (2003) analyzed the CSRP3 gene in 200 patients with hypertrophic cardiomyopathy (CMH; see 192600), 400 patients with CMD, and 500 controls, and identified 3 different mutations (600824.0002-600824.0004) that cosegregated with disease in 3 unrelated families with CMH (CMH12; 612124). All 3 mutations were located in exon 3 and predicted amino acid substitutions at highly conserved residues in the LIM1 domain, which is responsible for interaction with alpha-actinin (see 102575) and with certain muscle-specific transcription factors. No mutations were detected in the CMD patients or controls.
In 2 sibs who died of dilated cardiomyopathy and who were negative for mutation in 8 known cardiomyopathy genes, Mohapatra et al. (2003) identified heterozygosity for a missense mutation in the CSRP3 gene (K69R; 600824.0005).
Geier et al. (2008) sequenced exons 2 and 3 of the CSRP3 gene in 652 CMD and 354 CMH patients and 533 unrelated controls and identified 2 unrelated CMH probands with a missense mutation in CSRP3 (600824.0006). The authors also found the W4R variant (600824.0001), previously reported by Knoll et al. (2002) in 10 patients with dilated cardiomyopathy (CMD1M; 607482), in 3 CMD patients (0.5%), 2 CMH patients (0.6%), and 2 controls (0.4%); they concluded that the W4R variant is not sufficient to cause cardiomyopathy.
Arber et al. (1997) generated Csrp3 -/- mice and observed the development of dilated cardiomyopathy with hypertrophy and heart failure after birth. Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture, including myofibrillar disorganization. In vivo analysis revealed that Csrp3-deficient mice reproduce the morphologic and clinical picture of dilated cardiomyopathy and heart failure in humans. The authors stated that this was the first model for this condition in a genetically manipulatable organism.
This variant, formerly titled CARDIOMYOPATHY, DILATED, 1M (607482), has been reclassified based on the findings of Bos et al. (2006) and Geier et al. (2008).
Knoll et al. (2002) sequenced the entire MLP coding region in more than 50 patients with dilated cardiomyopathy (DCM) and identified 1 patient with a heterozygous T-to-C transition that led to a severe change, trp4 to arg (W4R), in the MLP protein. This mutation was located within the N-terminal TCAP (604488)-interacting domain (TID) of MLP, and the resulting form of DCM was designated CMD1M (607482). The 1-bp change introduced a Nci I restriction site, allowing subsequent rapid screening of 536 DCM patients, resulting in the identification of 9 additional patients with the identical heterozygous missense mutation in MLP. All positive patients were confirmed by direct sequencing of the TID region. Genetic analysis of the kindred of 3 DCM patients suggested a dominant form of disease transmission. Linkage analysis was carried out for 7 German DCM families, resulting in a combined 2-point lod score of 2.62. This analysis was limited by the size of pedigrees and age-dependent penetrance.
Bos et al. (2006) analyzed all translated exons of the CSRP3 gene in 389 unrelated CMH patients and identified heterozygosity for the W4R variant in 7 patients as well as in 1 of 400 reference alleles. One of the patients carrying the W4R variant also had a mutation in the MYBPC3 gene (600958), and 2 of them also had a mutation in the MYH7 gene (160760).
Geier et al. (2008) sequenced exons 2 and 3 of the CSRP3 gene in 652 CMD and 354 CMH patients and 533 unrelated controls and found the W4R variant in 3 CMD patients (0.5%), 2 CMH patients (0.6%), and 2 controls (0.4%). Affected individuals from 1 of the CMH families were subsequently found to carry a known MYBPC3 nonsense mutation, and there was no correlation between the presence of the W4R variant and the severity of the disease and/or progression to heart failure. Both controls harboring the W4R variant (61 and 75 years old, respectively) had a negative family history of heart failure. The authors concluded that W4R is not sufficient to cause cardiomyopathy.
In 4 affected members of a large family with hypertrophic cardiomyopathy (CMH12; 612124), who were negative for mutations in all known CMH genes, Geier et al. (2003) identified heterozygosity for a T-to-G transversion in exon 3 of the CSRP3 gene, resulting in a cys58-to-gly (C58G) substitution at a highly conserved residue in the LIM1 domain. Protein-binding studies revealed that the C58G mutation lead to decreased binding activity of MLP to alpha-actinin (see 102575). The mutation was not found in 400 patients with dilated cardiomyopathy (see 115200) or in 500 controls.
Geier et al. (2008) found that the C58G-mutant protein was less stable in solution than wildtype MLP, and that thermolysine digestion resulted in more rapid proteolysis of the mutant protein. The instability of C58G-mutant MLP was confirmed in transfected COS-1 cells, and RT-PCR showed that the relative lack of mutant MLP compared to wildtype was due to degradation of the mutated form.
In 3 brothers with hypertrophic cardiomyopathy (CMH12; 612124), Geier et al. (2003) identified heterozygosity for a T-to-C transition in exon 3 of the CSRP3 gene, resulting in a leu44-to-pro (L44P) substitution at a highly conserved residue in the LIM1 domain. The mutation was not found in 400 patients with dilated cardiomyopathy (see 115200) or in 500 controls.
In a brother and 2 sisters with hypertrophic cardiomyopathy (CMH12; 612124), Geier et al. (2003) identified heterozygosity for a mutation affecting 3 nucleotides, TCGGAG-to-AGGGGG, in exon 3 of the CSRP3 gene, resulting in adjacent ser54-to-arg (S54R) and glu55-to-gly (E55G) substitutions at highly conserved residues in the LIM1 domain. The mutation was not found in 400 patients with dilated cardiomyopathy (see 115200) or in 500 controls.
In 2 sibs who died of dilated cardiomyopathy (CMD1M; 607482), Mohapatra et al. (2003) identified heterozygosity for a 205A-G transition in exon 2 of the CSRP3 gene, resulting in substitution of arg at the highly conserved lys69 (K69R). Computer modeling predicted significant secondary structural changes, and coimmunoprecipitation studies showed that the K69R mutant CSRP3 did not bind ACTN2 (102573). The mutation was also found in the unaffected mother, but not in the unaffected father or 200 controls.
In 2 probands from unrelated families with hypertrophic cardiomyopathy (CMH12; 612124), Geier et al. (2008) identified heterozygosity for a 136A-C transversion in exon 3 of the CSRP3 gene, resulting in a ser46-to-arg (S46R) substitution at a highly conserved residue. The mutation cosegregated with disease in 1 family and was not found in the unaffected son of the other proband or in 533 unrelated controls. Although the 2 families were unrelated, haplotype analysis revealed that they may share a common ancestor.
Arber, S., Halder, G., Caroni, P. Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation. Cell 79: 221-231, 1994. [PubMed: 7954791] [Full Text: https://doi.org/10.1016/0092-8674(94)90192-9]
Arber, S., Hunter, J. J., Ross, J., Jr., Hongo, M., Sansig, G., Borg, J., Perriard, J.-C., Chien, K. R., Caroni, P. MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88: 393-403, 1997. [PubMed: 9039266] [Full Text: https://doi.org/10.1016/s0092-8674(00)81878-4]
Bos, J. M., Poley, R. N., Ny, M., Tester, D. J., Xu, X., Vatta, M., Towbin, J. A., Gersh, B. J., Ommen, S. R., Ackerman, M. J. Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin. Molec. Genet. Metab. 88: 78-85, 2006. [PubMed: 16352453] [Full Text: https://doi.org/10.1016/j.ymgme.2005.10.008]
Fung, Y. W., Wang, R. X., Heng, H. H. Q., Liew, C. C. Mapping of a human LIM protein (CLP) to human chromosome 11p15.1 by fluorescence in situ hybridization. Genomics 28: 602-603, 1995. [PubMed: 7490106] [Full Text: https://doi.org/10.1006/geno.1995.1200]
Geier, C., Gehmlich, K., Ehler, E., Hassfeld, S., Perrot, A., Hayess, K., Cardim, N., Wenzel, K., Erdmann, B., Krackhardt, F., Posch, M. G., Osterziel, K. J., and 9 others. Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy. Hum. Molec. Genet. 17: 2753-2765, 2008. Note: Erratum: Hum. Molec. Genet. 17: 3436 only, 2008. [PubMed: 18505755] [Full Text: https://doi.org/10.1093/hmg/ddn160]
Geier, C., Perrot, A., Ozcelik, C., Binner, P., Counsell, D., Hoffmann, K., Pilz, B., Martiniak, Y., Gehmlich, K., van der Ven, P. F. M., Furst, D. O., Vornwald, A., von Hodenberg, E., Nurnberg, P., Scheffold, T., Dietz, R., Osterziel, K. J. Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy. Circulation 107: 1390-1395, 2003. [PubMed: 12642359] [Full Text: https://doi.org/10.1161/01.cir.0000056522.82563.5f]
Knoll, R., Hoshijima, M., Hoffman, H. M., Person, V., Lorenzen-Schmidt, I., Bang, M.-L., Hayashi, T., Shiga, N., Yasukawa, H., Schaper, W., McKenna, W., Yokoyama, M., and 9 others. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111: 943-955, 2002. [PubMed: 12507422] [Full Text: https://doi.org/10.1016/s0092-8674(02)01226-6]
Kostek, M. C., Chen, Y.-W., Cuthbertson, D. J., Shi, R., Fedele, M. J., Esser, K. A., Rennie, M. J. Gene expression responses over 24 h to lengthening and shortening contractions in human muscle: major changes in CSRP3, MUSTN1, SIX1, and FBXO32. Physiol. Genomics 31: 42-52, 2007. [PubMed: 17519359] [Full Text: https://doi.org/10.1152/physiolgenomics.00151.2006]
Mohapatra, B., Jimenez, S., Lin, J. H., Bowles, K. R., Coveler, K. J., Marx, J. G., Chrisco, M. A., Murphy, R. T., Lurie, P. R., Schwartz, R. J., Elliott, P. M., Vatta, M., McKenna, W., Towbin, J. A., Bowles, N. E. Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis. Molec. Genet. Metab. 80: 207-215, 2003. [PubMed: 14567970] [Full Text: https://doi.org/10.1016/s1096-7192(03)00142-2]
Weiskirchen, R., Pino, J. D., Macalma, T., Bister, K., Beckerle, M. C. The cysteine-rich protein family of highly related LIM domain proteins. J. Biol. Chem. 270: 28946-28954, 1995. [PubMed: 7499425] [Full Text: https://doi.org/10.1074/jbc.270.48.28946]