PLN – Arrhythmogenic Right Ventricular Cardiomyopathy

Phospholamban (PLN) encodes a 52–amino acid regulator of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), crucial for cardiomyocyte calcium reuptake and contractility. Heterozygous PLN variants, most notably the arginine 14 deletion, have been repeatedly identified in patients meeting diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), supporting a dominant mode of inheritance. ARVC is characterized by ventricular arrhythmias, fibrofatty myocardial replacement, and risk of sudden cardiac death, with pathogenic PLN variants conferring a biventricular arrhythmogenic phenotype.

Genetic screening of 97 unrelated ARVC index patients revealed the founder PLN c.37AGA[1] (p.Arg14del) variant in 12 individuals (12 %) and demonstrated a common haplotype traceable to 575–825 years ago ([PMID:22820313]). In a cohort of 170 Chinese ARVC probands, six (3.5 %) carried the same p.Arg14del variant; family screening confirmed that heterozygous carriers exhibited a definitive ARVC phenotype ([PMID:38605909]). An early report described two affected siblings with ARVC and co-segregating PLN variants in a consanguineous family ([PMID:9409860]). No other PLN variants were detected in large ARVC panels, underscoring the specificity of p.Arg14del for this cardiomyopathy ([PMID:26917049]).

Segregation analysis includes two affected relatives in the original family report ([PMID:9409860]) and multiple multi-generational pedigrees with p.Arg14del demonstrating cosegregation of arrhythmogenic traits. The recurrent founder nature of p.Arg14del is further supported by haplotype and geographic analyses, with no evidence for de novo events in ARVC cohorts.

Functional studies in patient-derived induced pluripotent stem cell cardiomyocytes harboring p.Arg14del recapitulate abnormal calcium transients, electrical instability, and arrhythmogenic remodeling, all reversible upon targeted gene correction ([PMID:35700631]). A knock-in zebrafish model of p.Arg14del exhibits diastolic Ca2+ overload, action potential alternans, and age-dependent structural remodeling; istaroxime treatment ameliorates these phenotypes by normalizing Ca2+ dynamics ([PMID:34887420]). Immunofluorescence of explanted hearts from eight p.Arg14del carriers reveals a distinct desmosomal protein distribution compared with desmosomal ARVC, supporting a specific molecular signature ([PMID:30763825]).

Mechanistically, p.Arg14del disrupts PLN’s regulation of SERCA2a, leading to loss-of-function, dominant-negative effects, mislocalization to the sarcolemma, and perturbed Ca2+ homeostasis. The resultant cytosolic Ca2+ overload and fibrofatty replacement underpin the arrhythmogenic phenotype. These findings are concordant across cellular, animal, and human tissue models.

An international Clinical Genome Resource panel assigned PLN a “Moderate” level of evidence for ARVC causation in 2021, reflecting consistent genetic and experimental concordance but limited large-scale segregation data ([PMID:33831308]). No refuting studies have been reported.

Key Take-home: Heterozygous PLN p.Arg14del is a recurrent founder variant causing autosomal dominant ARVC via dominantly inherited loss of SERCA2a regulation, with clear diagnostic and therapeutic implications.

References

• American journal of medical genetics • 1997 • Arrhythmogenic right ventricular dysplasia and anterior polar cataract. PMID:9409860
• European journal of heart failure • 2012 • Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. PMID:22820313
• Phenomics (Cham, Switzerland) • 2024 • A Heterozygous Phospholamban Variant (p.R14del) Leads to Left Ventricular Involvement and Heart Failure Phenotypes in Arrhythmogenic Right Ventricular Cardiomyopathy. PMID:38605909
• Stem cell research • 2022 • Generation of two induced pluripotent stem cell lines carrying the phospholamban R14del mutation for modeling ARVD/C. PMID:35700631
• Nature communications • 2021 • Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model of phospholamban R14del cardiomyopathy. PMID:34887420
• Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology • 2019 • Distinct molecular signature of phospholamban p.Arg14del arrhythmogenic cardiomyopathy. PMID:30763825
• Circulation. Genomic and precision medicine • 2021 • International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework. PMID:33831308

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