rs104894797 — DMD Arg3182Ter (R3182*)

The Dystrophin Arg3182Ter Variant — X-Linked Cardiac Disease Without Muscle Warning Signs

Dystrophin is the largest protein-coding gene in the human genome — 2.3 megabases on the X chromosome, encoding a 427 kDa mechanical scaffolding protein that anchors the interior of muscle cells to the surrounding extracellular matrix. Without functional dystrophin, repeated mechanical stress from muscle contraction tears the cell membrane, triggering calcium influx, inflammatory cascades, and progressive cell death. The resulting condition is usually Duchenne muscular dystrophy (DMD) — severe, childhood-onset, wheelchair-confining skeletal muscle disease. But certain DMD variants, including this one, can cause cardiac muscle destruction with minimal or no skeletal muscle involvement, producing a clinical picture that can be mistaken for ordinary idiopathic dilated cardiomyopathy¹¹ dilated cardiomyopathy
A form of heart failure in which the heart muscle weakens and the chambers enlarge, reducing pumping efficiency.

The Arg3182Ter variant (c.9544C>T on the coding strand; NC_000023.11:g.31206663G>A on the GRCh38 plus strand) introduces a premature stop codon at position 3182 of the dystrophin protein, truncating the C-terminal domain and eliminating the protein's ability to anchor properly to the cytoskeleton. The stop is classified as pathogenic in ClinVar (RCV000150055) with associations to Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy (XLCM).

The Mechanism

Dystrophin connects intracellular actin filaments to the dystrophin-associated glycoprotein complex (DAGC) on the sarcolemma, which in turn connects to laminin in the extracellular matrix. In cardiac muscle, dystrophin loss destabilizes this mechanical linkage across the entire myocardium with every heartbeat — roughly 3 billion contractions over a lifetime. The pathological cascade involves three overlapping mechanisms identified in Kamdar & Garry's review²² Kamdar & Garry's review
J Am Coll Cardiol 2016: abnormal calcium influx through membrane micro-tears activating destructive proteases; mis-localization of neuronal nitric oxide synthase (nNOS)³³ mis-localization of neuronal nitric oxide synthase (nNOS)
Without dystrophin, nNOS cannot bind to the sarcolemma; free cytoplasmic nNOS generates excess reactive nitrogen species and impairs excitation-contraction coupling; and mitochondrial dysfunction leading to ATP depletion and oxidative stress.

Nonsense mutations near the C-terminus of dystrophin, like Arg3182Ter, may permit expression of shorter dystrophin isoforms (Dp260, Dp140, Dp116, Dp71) that retain their own promoters upstream of the truncation. Cardiac muscle expresses multiple isoforms with different promoters, and the balance of which isoforms are preserved determines whether skeletal muscle symptoms precede, coincide with, or never appear alongside the cardiac disease. This isoform-dependent phenotypic variation explains why some carriers present with classic DMD/BMD while others develop what appears to be isolated XLCM.

The Evidence

A landmark multicenter European study of 223 DMD mutation carriers⁴⁴ multicenter European study of 223 DMD mutation carriers
Restrepo-Cordoba et al., Eur J Heart Fail, 2021 found that 52% developed dilated cardiomyopathy, with DCM appearing earlier in males and independently of mutation type, skeletal muscle disease severity, or creatine kinase elevation. Among those who developed DCM, 22% experienced major adverse cardiac events, 18% progressed to end-stage heart failure, and 9% suffered sudden cardiac death. Critically, carriers without DCM had favorable outcomes with no major events — establishing cardiac monitoring as the intervention that determines prognosis.

The most important evidence for management comes from the Duboc et al. perindopril trials⁵⁵ Duboc et al. perindopril trials
J Am Coll Cardiol 2005 and Am Heart J 2007. A randomized trial of 57 DMD children with normal baseline cardiac function found that early perindopril treatment reduced the number developing severely reduced LVEF (<45%) from 8 to 1 patient at five years (p=0.02). At the 10-year follow-up⁶⁶ 10-year follow-up
Duboc et al., Am Heart J, 2007, survival was 92.9% in the perindopril group versus 65.5% in controls (p=0.02) — a dramatic mortality difference from initiating an ACE inhibitor before any cardiac dysfunction appeared.

A 2023 case report⁷⁷ 2023 case report
Ohtani et al., Intern Med, 2023 documented a 56-year-old woman with treatment-resistant DCM and no skeletal muscle symptoms whose underlying cause — a DMD exon duplication — was identified only through careful family history (male relatives dying of Duchenne MD). The authors note that "careful family history interviews and investigation of dystrophinopathy are required to detect XLCM in women."

Practical Actions

For affected males (hemizygous): cardiac disease is the primary cause of morbidity and mortality, and it can progress silently until a catastrophic event. Annual ECG and echocardiography from diagnosis, with cardiac MRI for detecting early subepicardial fibrosis before LVEF decline, are the surveillance standard. ACE inhibitor or ARB therapy should begin before cardiac dysfunction is detectable — the perindopril trials demonstrate that this prophylactic approach dramatically changes survival. ACE inhibitor and beta-blocker therapy complement each other; the Cochrane review found ACE inhibitors and ARBs comparably effective, with the mineralocorticoid antagonist eplerenone slowing further strain deterioration as a useful add-on.

For female carriers: isolated X-linked dilated cardiomyopathy is a documented presentation in female DMD carriers. Cardiac surveillance beginning by age 40 — or earlier if symptoms arise — is essential. A family history of DMD-affected males is the critical screening trigger in women presenting with unexplained DCM.

Interactions

DMD follows X-linked inheritance: an affected hemizygous male (genotype AA in our notation) has one copy on his single X chromosome. A female carrier (genotype AG) has one functional and one truncated allele; random X-inactivation in cardiac tissue determines what proportion of cardiomyocytes express wild-type versus Arg3182Ter dystrophin. Females with skewed X-inactivation favoring the variant-bearing chromosome may develop earlier or more severe cardiac involvement. Cascade testing of first-degree relatives is clinically indicated: all daughters of an affected male are obligate carriers; each son of a carrier female has a 50% chance of being affected.

There are no documented gene-gene interactions that modify management for this specific variant. Cardiac risk from Arg3182Ter is driven entirely by dystrophin loss in the myocardium and is not meaningfully modified by variants in other genes.