rs397516923 — DSP DSP Q72Ter

Desmoplakin's Hidden Role in the Heart — When the Cellular Glue Fails

Desmoplakin is the molecular anchor that holds heart muscle cells together. Encoded by the DSP gene¹¹ DSP gene
Desmoplakin, chromosome 6p24.3; encodes the largest desmosomal protein at 2,871 amino acids, it forms the cytoplasmic half of desmosomes²² desmosomes
Specialized cell-cell junctions that anchor intermediate filaments across adjacent cells, providing tensile strength in tissues under repeated mechanical stress. In the heart, where each cell is pulled and squeezed with every beat, intact desmosomes are not optional — they are structural lifelines. The rs397516923 variant (c.214C>T) creates a premature stop codon at position 72 of the desmoplakin protein (p.Gln72Ter), truncating the protein before it can serve any structural function. The resulting haploinsufficiency — one broken copy in a dominant condition — is sufficient to compromise cardiac desmosomal integrity and predispose carriers to a fibrotic, inflammatory form of cardiomyopathy.

The Mechanism

Normally, desmoplakin bridges between the desmosomal plaque proteins (plakophilin, plakoglobin) and the intermediate filament cytoskeleton (desmin), anchoring the cellular scaffold across the gap junction. When one DSP allele carries a nonsense variant³³ nonsense variant
A single-nucleotide change that converts an amino acid codon into a stop codon, terminating translation prematurely; here at residue 72 of 2,871, leaving over 97% of the protein unproduced, the truncated mRNA is typically eliminated by nonsense-mediated mRNA decay (NMD)⁴⁴ nonsense-mediated mRNA decay (NMD)
A cellular surveillance mechanism that degrades mRNAs containing premature stop codons, usually preventing production of a truncated protein that might interfere with the normal copy. The remaining wild-type allele produces only half the normal desmoplakin, insufficient to maintain normal desmosomal density. The consequence is progressive replacement of cardiomyocytes with fibrofatty tissue — particularly in the left ventricular subepicardium — along with arrhythmogenic scarring.

Notably, DSP-related cardiomyopathy differs from classic arrhythmogenic right ventricular cardiomyopathy (ARVC): DSP truncating variants cause predominantly left ventricular or biventricular disease. A landmark study found 55% of DSP variant carriers⁵⁵ 55% of DSP variant carriers
Smith et al. Circulation 2020 — 107 patients with pathogenic DSP mutations versus 81 PKP2-mutation patients showed left ventricular predominance, compared to 0% of PKP2 mutation carriers. This LV-centric phenotype means the condition is frequently misdiagnosed as myocarditis or dilated cardiomyopathy.

The Evidence

ClinVar classifies rs397516923 as pathogenic (VCV000044872.7), supported by functional and clinical evidence that loss-of-function variants in DSP cause arrhythmogenic cardiomyopathy. The p.Gln72Ter truncation is among the earliest-terminating DSP nonsense variants documented in clinical cohorts, and variant location matters: Hoorntje et al. 2023⁶⁶ Hoorntje et al. 2023
Circ Genomic and Precision Medicine — 170 DSP truncating variant carriers, mean age at diagnosis 43 years found that variants triggering NMD of both major DSP isoforms occurred in 83.6% of high-arrhythmic-risk cases versus only 16.4% of low-risk cases (p<0.0001), and 33% of carriers overall experienced sustained ventricular arrhythmia during follow-up.

The largest outcomes dataset to date enrolled 800 DSP variant carriers across 34 institutions⁷⁷ 800 DSP variant carriers across 34 institutions
Gasperetti et al. Eur Heart J 2025 — multinational registry, median follow-up 3.7 years: 17.4% developed sustained ventricular arrhythmia at 3.9% per year; 9% required hospitalization for heart failure. Left ventricular ejection fraction (LVEF) below 50% was independently associated with both arrhythmic risk (HR 1.645) and heart failure risk (HR 3.879). Acute myocardial injury episodes — occurring in 8.8% of patients — doubled subsequent arrhythmia risk and raised heart failure risk five-fold.

In pediatric carriers, the condition is particularly aggressive: a 34-patient pediatric cohort⁸⁸ 34-patient pediatric cohort
Choi et al. Circ Arrhythm Electrophysiol 2024 found 50% of ICD recipients received appropriate shocks, and the condition mimicked myocarditis at presentation in half of symptomatic patients — elevating the risk of delayed or missed diagnosis.

The inheritance pattern is autosomal dominant with reduced penetrance. Not all carriers develop overt disease, but the pathogenic classification of this specific variant reflects documented co-segregation with cardiomyopathy in affected families.

Practical Actions

For carriers of this variant, cardiac evaluation is the priority. Standard ARVC risk calculators perform poorly in DSP carriers (c-statistic 0.558 for LV-predominant disease), making individual assessment by a cardiomyopathy specialist essential. Key monitoring elements include cardiac MRI with late gadolinium enhancement (the primary test for subepicardial LV fibrosis), Holter monitoring for ventricular ectopy, and periodic echocardiography for ejection fraction surveillance.

High-intensity competitive sports should be avoided, as exercise-induced ventricular ectopy is more frequent in desmosomal mutation carriers and endurance exercise accelerates the fibrofatty remodeling that drives arrhythmic risk. First-degree relatives (parents, siblings, children) should undergo genetic cascade testing and, if variant-negative, clinical surveillance screening every 1-3 years from age 10 given the condition's age-dependent penetrance.

Interactions

DSP-related cardiomyopathy may interact with other desmosomal gene variants. Compound heterozygosity for two DSP alleles (one from each parent) produces a more severe phenotype with earlier onset and dermatologic manifestations (woolly hair, palmoplantar keratoderma) as seen in Carvajal syndrome. Variants in co-desmosomal proteins — PKP2, DSG2, DSC2, JUP — have independent pathogenic roles and may compound with DSP haploinsufficiency in rare cases. Family members sharing additional desmosomal variant burden appear to have worse clinical trajectories than those carrying only the DSP truncating allele.