HGNC Approved Gene Symbol: PLN
Cytogenetic location: 6q22.31 Genomic coordinates (GRCh38) : 6:118,548,296-118,561,716 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q22.31 | Cardiomyopathy, dilated, 1P | 609909 | 3 | |
| Cardiomyopathy, hypertrophic, 18 | 613874 | Autosomal dominant | 3 |
Phospholamban is expressed in the sarcoplasmic reticulum membrane as a 30-kD homopentamer. It controls cellular calcium levels by a mechanism that depends on its phosphorylation (summary by Oxenoid and Chou, 2005).
Using dog and rabbit phospholamban cDNAs as probes, Fujii et al. (1991) cloned human phospholamban from a skeletal muscle cDNA library. The deduced 52-amino acid human protein differs from rabbit, dog, and pig at position 27 and from dog and pig at position 2. Northern blot analysis of rabbit tissues detected phospholamban transcripts in heart and soleus and in tissues rich in smooth muscle, such as uterus, small and large intestine, trachea, bladder, esophagus, and aorta. No expression was detected in plantaris, spleen, testis, brain, liver, and kidney.
McTiernan et al. (1999) found that human ventricle and quadriceps displayed high levels of phospholamban transcripts and proteins, with markedly lower expression in smooth muscles. The right atrium also expressed low levels of phospholamban.
Fujii et al. (1991) found that the rabbit Pln gene spans 13.2 kb and contains only 1 intron, which separates exonic sequences in the 5-prime UTR.
McTiernan et al. (1999) reported that the structure of the human phospholamban gene closely resembles that reported for the chicken, rabbit, rat, and mouse genes. Comparison of the human to other mammalian phospholamban genes indicated a marked conservation of sequence for at least 217 bp upstream of the transcription start site.
Using a human phospholamban cDNA, Fujii et al. (1991) mapped the phospholamban gene to human chromosome 6. By fluorescence in situ hybridization, Otsu et al. (1993) mapped the PLN gene to chromosome 6q22.1.
Fujii et al. (1991) stated that phospholamban is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. Phospholamban is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a; see 108740) in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta agonists. Phospholamban is also expressed in slow-twitch skeletal muscle and some smooth muscle cells.
Asahi et al. (2004) generated mice with cardiac-specific overexpression of epitope-tagged rabbit sarcolipin (SLN; 602203). Overexpression of Sln decreased the apparent affinity of Serca2a (108740) for calcium in transgenic hearts. The mice had altered calcium currents, impaired cardiac contractility with altered tension and relaxation times, and ventricular hypertrophy. Coimmunoprecipitation indicated that overexpressed Sln bound both Serca2a and Pln, forming a ternary complex. The results suggested that Sln overexpression inhibits Serca2a through stabilization of Serca2a-Pln interaction and through inhibition of Pln phosphorylation. Asahi et al. (2004) concluded that inhibition of Serca2a impairs contractility and calcium cycling, but responsiveness to beta-adrenergic agonists may prevent progression to heart failure.
By pairwise testing of fluorescence-labeled proteins, Phillips et al. (2023) showed that different SERCA-modulating membrane micropeptides, including PLN, formed heterooligomers with varying affinities. Moreover, each micropeptide also assembled into homooligomers, but the homooligomers did not interact with SERCA. The affinities of heterooligomerization of micropeptides depended on whether they were the minority or majority species, and SERCA interaction with individual monomeric micropeptides competed with micropeptide-micropeptide interactions.
Using NMR experiments, Oxenoid and Chou (2005) characterized the reconstituted human PLN pentamer. They found that PLN assembled by parallel packing into well-structured pentamers with 5-fold rotational symmetry. In the PLN pentamer, the positively-charged N-terminal domains formed alpha helices that repulsed one another via electrostatic charges and assumed a bellflower appearance. The linker regions of each subunit acquired dihedral angles characteristic of beta strands. The long, largely hydrophobic C-terminal transmembrane alpha helices engaged in leu/ile zipper interactions and formed a funnel-like pore with a diameter of about 3.6 angstroms at its narrowest point. Oxenoid and Chou (2005) concluded that, like monomeric PLN, pentameric PLN can interact with the SERCA cytoplasmic domain due to the relative mobility of the N-terminal SERCA-interacting domains. They proposed that the entire PLN pentamer may have a dual function as a regulatory protein and as an ion channel.
Dilated Cardiomyopathy 1P
Schmitt et al. (2003) sequenced the PLN gene in 20 unrelated individuals with inherited dilated cardiomyopathy and heart failure (see CMD1P, 609909). In 1 sample, an arginine-to-cysteine substitution at codon 9 in the cytosolic PLN domain was identified and segregated with disease in that 4-generation family (R9C; 172405.0001). Affected individuals had increased chamber dimensions and decreased contractile function at age 20 to 30 years, with progression to heart failure within 5 to 10 years after symptom onset. Congestive heart failure was severe in 12 individuals, necessitating cardiac transplantation in 4. The average age at death of affected individuals was 25.1 +/- 12.7 years.
In 2 unrelated families with CMD1P, Haghighi et al. (2003) identified a nonsense mutation in the PLN gene (L39X; 172405.0002). The 2 homozygous individuals developed dilated cardiomyopathy and heart failure requiring cardiac transplantation at ages 16 and 27 years, respectively; 11 heterozygous individuals exhibited variable clinical findings, indicating incomplete penetrance of the cardiomyopathy phenotype. Haghighi et al. (2003) concluded that in contrast to mice in which Pln deficiency enhances myocardial inotropy and lusitropy without adverse effects, PLN is essential for cardiac health in humans, and its absence results in lethal heart failure.
In affected members of a 7-generation family with CMD1P, Haghighi et al. (2006) identified heterozygosity for a 3-bp deletion in the PLN gene (172405.0003).
Haghighi et al. (2008) analyzed the PLN gene in 381 CMD patients and 296 controls with no known cardiomyopathy history and identified a heterozygous -36A-C variant in the 5-prime untranslated region (172405.0006) in 22 patients and 1 control. Functional analysis demonstrated that the -36A-C variant increased PLN activity by 24% compared to wildtype and that this alteration in the steroid receptor sequence for the glucocorticoid nuclear receptor/transcription factor resulted in enhanced binding.
Hypertrophic Cardiomyopathy 18
Minamisawa et al. (2003) analyzed the candidate gene PLN in 87 patients with hypertrophic cardiomyopathy (see CMH18; 613874), 10 with dilated cardiomyopathy, and 2 patients with restrictive cardiomyopathy (RCM; see 115210). In the proband of a 2-generation family with CMH, they identified heterozygosity for a mutation in the promoter region (172405.0004) that increased transcriptional activity 1.5-fold compared to wildtype and was not found in 296 Japanese controls. No PLN mutations were identified in the remaining 98 cardiomyopathy patients.
Medin et al. (2007) performed SSCP mutation screening and DNA sequencing of the PLN gene in 101 CMH patients and 85 CMD patients and identified a point mutation in the promoter region (172405.0005) in 1 CMH proband.
Chiu et al. (2007) screened an Australian cohort of 252 unrelated CMH patients for mutations in calcium regulatory genes and identified heterozygosity for the L39X mutation in the PLN gene in 1 proband (172405.0002).
Landstrom et al. (2011) analyzed the PLN gene in a cohort of 1,064 CMH probands and identified heterozygosity for the L39X mutation in a 58-year-old male proband with CMH.
Exclusion Studies
Kalemi et al. (2005) did not find mutations in the PLN gene in 53 Greek patients with CMH, but noted that because 95% of identified CMH-related mutations involve 4 genes, namely MYH7 (160760), TNNT2 (191045), MYBPC3 (600958), and TNNI3 (191044), a large cohort of CMH patients would be required to identify a novel CMH-causing gene.
Petkow-Dimitrow et al. (2011) screened 50 consecutive patients with CMH from southern Poland for the R9C (172405.0001) and L39X (172405.0002) mutations in the PLN gene but did not find those mutations in any patients or in 50 sex- and age-matched controls with normal echocardiograms.
Luo et al. (1994) generated Pln -/- mice, which exhibited significantly enhanced myocardial performance that was associated with an increase in the affinity of Serca2 for Ca(2+). Isoproterenol dose-response curves for contraction and relaxation in the Pln-null mice began at a maximum level and were not further increased by isoproterenol. Luo et al. (1994) concluded that PLN acts as a critical repressor of basal myocardial contractility and may be the key phosphoprotein mediating in cardiac contractile responses to beta-adrenergic agonists.
Using echocardiography to assess left ventricular function in Pln-null mice in vivo, Hoit et al. (1995) observed significant increases in multiple physiologic parameters compared to wildtype controls (p less than 0.05) and concluded that PLN regulates basal left ventricular function in vivo.
In a hamster model of progressive heart failure, Hoshijima et al. (2002) used an in vivo transcoronary delivery system to administer recombinant adeno-associated virus expressing a pseudophosphorylated mutant of human PLN. The treatment suppressed progressive impairment of left ventricular systolic function and contractility for 28 to 30 weeks; low left ventricular systolic pressure and deterioration in left ventricular relaxation were also largely prevented, protecting the hamsters from myocardial cell loss.
Schmitt et al. (2003) generated transgenic mice expressing the PLN R9C mutation under the control of the alpha-cardiac myosin heavy chain (160710) promoter. Two independent lines with identical phenotype were generated: biventricular cardiac dilation began at age 4 months, and dilated cardiomyopathy was rapidly progressive. Cellular and biochemical studies revealed that, unlike wildtype PLN, PLN-R9C did not directly inhibit SERCA2a. Rather, PLN-R9C trapped protein kinase A (see 176911), which blocked PKA-mediated phosphorylation of wildtype PLN and in turn delayed decay of calcium transients in myocytes. Schmitt et al. (2003) concluded that myocellular calcium dysregulation can initiate human heart failure.
In transgenic mice with cardiac-specific overexpression of the PLN arg14 deletion, Haghighi et al. (2006) observed recapitulation of human cardiomyopathy, with similar histopathologic abnormalities and premature death. Coexpression of normal and mutant PLN in HEK293 cells resulted in superinhibition of sarcoplasmic reticulum Ca(2+)-ATPase activity, and the dominant effect of the arg14 deletion could not be fully removed, even upon phosphorylation by protein kinase A (see 176911).
In a 4-generation family segregating autosomal dominant dilated cardiomyopathy with heart failure (CMD1P; 609909), Schmitt et al. (2003) identified a C-to-T transition at nucleotide 25 of the PLN gene, resulting in an arg9-to-cys (R9C) substitution in the cytosolic PLN domain. This mutation segregated absolutely with affected status in the family, occurred in a highly conserved residue, and was absent from more than 200 normal chromosomes. In the family, affected individuals had increased chamber dimensions and decreased contractile function at age 20 to 30 years, with progression to heart failure within 5 to 10 years after symptom onset. Congestive heart failure was severe in 12 individuals, necessitating cardiac transplantation in 4. The average age at death in affected individuals was 25.1 +/- 12.7 years.
Using biochemical and biophysical techniques in vitro and in live cells, Ha et al. (2011) found that the R9C mutation led to stabilization of pentameric PLN due to disulfide bridge formation between the cytoplasmic domains of individual PLN(R9C) subunits. Stabilization of the PLN pentamer inhibited the dissociation of the pentamer into PLN monomers and promoted the formation of PLN(R9C) dimers, particularly under oxidative conditions. PKA (see 176911)-mediated phosphorylation of pentameric PLN(R9C) was significantly impaired due to this stabilization.
Dilated Cardiomyopathy 1P
In 2 unrelated families with idiopathic dilated cardiomyopathy (CMD1P; 609909), Haghighi et al. (2003) identified a 116T-G transversion in the PLN gene, resulting in a leu39-to-ter (L39X) substitution that truncated the 52-amino acid protein in the highly conserved transmembrane domain II. The 2 homozygous individuals developed dilated cardiomyopathy and heart failure requiring cardiac transplantation at ages 16 and 27 years, respectively; 11 heterozygous individuals exhibited variable clinical findings indicating incomplete penetrance of the cardiomyopathy phenotype: 2 had dilated cardiomyopathy with ejection fractions of 25% or less, 4 had left ventricular hypertrophy with normal left ventricular systolic function, and 5 had normal echocardiograms.
Hypertrophic Cardiomyopathy 18
In a 65-year-old Australian woman who was diagnosed with familial hypertrophic cardiomyopathy (CMH18; 613874) at age 61 years, Chiu et al. (2007) identified heterozygosity for the L39X mutation in the PLN gene. Echocardiography revealed asymmetric septal hypertrophy with a maximum wall thickness of 20 mm, normal systolic contractile function, and no evidence of left ventricular dilation. Her mother had also been diagnosed with CMH and had died at age 80 of noncardiac causes.
In a 58-year-old man with CMH18, Landstrom et al. (2011) identified heterozygosity for the L39X mutation in the PLN gene. The mutation segregated with disease in the family and was not found in 300 controls.
In a 7-generation family with idiopathic dilated cardiomyopathy (CMD1P; 609909) and ventricular tachycardia, Haghighi et al. (2006) identified heterozygosity for a 3-bp deletion in the PLN gene, resulting in deletion of a highly conserved arg14 residue. By middle age, heterozygous individuals in this family developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases. No homozygous individuals were identified.
In a woman who was diagnosed with hypertrophic cardiomyopathy (CMH18; 613874) at 56 years of age, Minamisawa et al. (2003) identified heterozygosity for a -77A-G transition in the promoter region of the PLN gene. Functional analysis in transiently transfected neonatal rat cardiomyocytes demonstrated that the mutation resulted in a 1.5-fold increase in PLN transcription compared to wildtype. The mutation was not found in 296 Japanese controls. The proband's family history was consistent with a late-onset type of CMH: her father, who was diagnosed with cardiomyopathy, had died at age 82, and an older brother was also diagnosed with CMH at age 62 years. None of the family members were available for study.
In an 85-year-old woman who was diagnosed with apical hypertrophic cardiomyopathy (CMH18; 613874) at 67 years of age, Medin et al. (2007) identified heterozygosity for a -42C-G transversion n the promoter region of the PLN gene that was not found in more than 100 control subjects. Mutations in 6 other known CMH genes were excluded in the proband. Transfection studies in the C6 glioma cell line and C2C12 muscle cells demonstrated a 43% and 47% decrease in transcriptional activity compared to wildtype, respectively. The proband's brother was diagnosed with apical CMH at 72 years of age and died suddenly at age 81 years. Screening of the proband's 3 asymptomatic sons revealed that 1 had apical hypertrophic cardiomyopathy with mild hypertrophy at age 59 years; the other 2 had normal electro- and echocardiograms. The affected son and a 55-year-old asymptomatic son were also heterozygous for the -42C-G mutation.
Haghighi et al. (2008) analyzed the PLN gene in 381 dilated cardiomyopathy patients and 296 controls with no known cardiomyopathy history and identified a heterozygous -36A-C transversion in the PLN promoter region in 22 patients with dilated cardiomyopathy-1P (CMD1P; 609909) and 1 control. Luciferase reporter analysis in rat neonatal cardiomyocytes demonstrated that the -36A-C variant increased PLN activity by 24% compared to wildtype. In addition, the -36A-C alteration in the steroid receptor sequence for the glucocorticoid nuclear receptor/transcription factor resulted in enhanced binding. Haghighi et al. (2008) suggested that this variant might contribute to depressed contractility and accelerate functional deterioration in heart failure.
Asahi, M., Otsu, K., Nakayama, H., Hikoso, S., Takeda, T., Gramolini, A. O., Trivieri, M. G., Oudit, G. Y., Morita, T., Kusakari, Y., Hirano, S., Hongo, K., Hirotani, S., Yamaguchi, O., Peterson, A., Backx, P. H., Kurihara, S., Hori, M., MacLennan, D. H. Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) activity and impairs cardiac function in mice. Proc. Nat. Acad. Sci. 101: 9199-9204, 2004. [PubMed: 15201433] [Full Text: https://doi.org/10.1073/pnas.0402596101]
Chiu, C., Tebo, M., Ingles, J., Yeates, L., Arthur, J. W., Lind, J. M., Semsarian, C. Genetic screening of calcium regulation genes in familial hypertrophic cardiomyopathy. J. Molec. Cell. Cardiol. 43: 337-343, 2007. [PubMed: 17655857] [Full Text: https://doi.org/10.1016/j.yjmcc.2007.06.009]
Fujii, J., Zarain-Herzberg, A., Willard, H. F., Tada, M., MacLennan, D. H. Structure of the rabbit phospholamban gene, cloning of the human cDNA, and assignment of the gene to human chromosome 6. J. Biol. Chem. 266: 11669-11675, 1991. [PubMed: 1828805]
Ha, K. N., Masterson, L. R., Hou, Z., Verardi, R., Walsh, N., Veglia, G., Robia, S. L. Lethal arg9cys phospholamban mutation hinders Ca(2+)-ATPase regulation and phosphorylation by protein kinase A. Proc. Nat. Acad. Sci. 108: 2735-2740, 2011. [PubMed: 21282613] [Full Text: https://doi.org/10.1073/pnas.1013987108]
Haghighi, K., Chen, G., Sato, Y., Fan, G.-C., He, S., Kolokathis, F., Pater, L., Paraskevaidis, I., Jones, W. K., Dorn, G. W., II, Kremastinos, D. T., Kranias, E. G. A human phospholamban promoter polymorphism in dilated cardiomyopathy alters transcriptional regulation by glucocorticoids. Hum. Mutat. 29: 640-647, 2008. [PubMed: 18241046] [Full Text: https://doi.org/10.1002/humu.20692]
Haghighi, K., Kolokathis, F., Gamolini, A. O., Waggoner, J. R., Pater, L., Lynch, R. A., Fan, G.-C., Tsiapras, D., Parekh, R. R., Dorn, G. W., II, MacLennan, D. H., Kremastinos, D. T., Kranias, E. G. A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc. Nat. Acad. Sci. 103: 1388-1393, 2006. [PubMed: 16432188] [Full Text: https://doi.org/10.1073/pnas.0510519103]
Haghighi, K., Kolokathis, F., Pater, L., Lynch, R. A., Asahi, M., Gramolini, A. O., Fan, G.-C., Tsiapras, D., Hahn, H. S., Adamopoulos, S., Liggett, S. B., Dorn, G. W., II, MacLennan, D. H., Kremastinos, D. T., Kranias, E. G. Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. J. Clin. Invest. 111: 869-876, 2003. [PubMed: 12639993] [Full Text: https://doi.org/10.1172/JCI17892]
Hoit, B. D., Khoury, S. F., Kranias, E. G., Ball, N., Walsh, R. A. In vivo echocardiographic detection of enhanced left ventricular function in gene-targeted mice with phospholamban deficiency. Circ. Res. 77: 632-637, 1995. [PubMed: 7641333] [Full Text: https://doi.org/10.1161/01.res.77.3.632]
Hoshijima, M., Ikeda, Y., Iwanaga, Y., Minamisawa, S, Date, M., Gu, Y., Iwatate, M., Li, M., Wang, L., Wilson, J. M., Wang, Y., Ross, J., Jr., Chien, K. R. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nature Med. 8: 864-871, 2002. [PubMed: 12134142] [Full Text: https://doi.org/10.1038/nm739]
Kalemi, T., Efthimiadis, G., Zioutas, D., Lambropoulos, A., Mitakidou, A., Giannakoulas, G., Vassilikos, V., Karvounis, H., Kotsis, A., Parharidis, G., Louridas, G. Phospholamban gene mutations are not associated with hypertrophic cardiomyopathy in a northern Greek population. Biochem. Genet. 43: 637-642, 2005. [PubMed: 16382369] [Full Text: https://doi.org/10.1007/s10528-005-9121-8]
Landstrom, A. P., Adekola, B. A., Bos, J. M., Ommen, S. R., Ackerman, M. J. PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing. Am. Heart J. 161: 165-171, 2011. [PubMed: 21167350] [Full Text: https://doi.org/10.1016/j.ahj.2010.08.001]
Luo, W., Grupp, I. L., Harrer, J., Ponniah, S., Grupp, G., Duffy, J. J., Doetschman, T., Kranias, E. G. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta-agonist stimulation. Circ. Res. 75: 401-409, 1994. [PubMed: 8062415] [Full Text: https://doi.org/10.1161/01.res.75.3.401]
McTiernan, C. F., Frye, C. S., Lemster, B. H., Kinder, E. A., Ogletree-Hughes, M. L., Moravec, C. S., Feldman, A. M. The human phospholamban gene: structure and expression. J. Molec. Cell Cardiol. 31: 679-692, 1999. [PubMed: 10198197] [Full Text: https://doi.org/10.1006/jmcc.1998.0904]
Medin, M., Hermida-Prieto, M., Monserrat, L., Laredo, R., Rodriguez-Rey, J. C., Fernandez, X., Castro-Beiras, A. Mutational screening of phospholamban gene in hypertrophic and idiopathic dilated cardiomyopathy and functional study of the PLN 42C-G mutation. Europ. J. Heart Fail. 9: 37-43, 2007. [PubMed: 16829191] [Full Text: https://doi.org/10.1016/j.ejheart.2006.04.007]
Minamisawa, S., Sato, Y., Tatsuguchi, Y., Fujino, T., Imamura, S., Uetsuka, Y., Nakazawa, M., Matsuoka, R. Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy. Biochem. Biophys. Res. Commun. 304: 1-4, 2003. [PubMed: 12705874] [Full Text: https://doi.org/10.1016/s0006-291x(03)00526-6]
Otsu, K., Fujii, J., Periasamy, M., Difilippantonio, M., Uppender, M., Ward, D. C., MacLennan, D. H. Chromosome mapping of five human cardiac and skeletal muscle sarcoplasmic reticulum protein genes. Genomics 17: 507-509, 1993. [PubMed: 8406504] [Full Text: https://doi.org/10.1006/geno.1993.1357]
Oxenoid, K., Chou, J. J. The structure of phospholamban pentamer reveals a channel-like architecture in membranes. Proc. Nat. Acad. Sci. 102: 10870-10875, 2005. [PubMed: 16043693] [Full Text: https://doi.org/10.1073/pnas.0504920102]
Petkow-Dimitrow, P., Kiec-Wilk, B., Kwasniak, M., Mikolajczyk, M., Dembinska-Kiec, A. Phospholamban gene mutations are not associated with hypertrophic cardiomyopathy in patients from southern Poland. Kardiol. Pol. 69: 134-137, 2011. [PubMed: 21332051]
Phillips, T. A., Hauck, G. T., Pribadi, M. P., Cho, E. E., Cleary, S. R., Robia, S. L. Micropeptide hetero-oligomerization adds complexity to the calcium pump regulatory network. Biophys. J. 122: 301-309, 2023. [PubMed: 36523160] [Full Text: https://doi.org/10.1016/j.bpj.2022.12.014]
Schmitt, J. P., Kamisago, M., Asahi, M., Li, G. H., Ahmad, F., Mende, U., Kranias, E. G., MacLennan, D. H., Seidman, J. G., Seidman, C. E. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299: 1410-1413, 2003. [PubMed: 12610310] [Full Text: https://doi.org/10.1126/science.1081578]