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Related Concept Videos

Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

380
Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
380
Cardiomyopathy I: Introduction and Classification01:25

Cardiomyopathy I: Introduction and Classification

488
Cardiomyopathy, or CMP, is a group of diseases affecting the myocardial structure, impairing its ability to pump blood effectively. This condition can lead to arrhythmias, heart failure, or sudden cardiac death.Cardiomyopathies are classified into primary and secondary categories:Primary Cardiomyopathy refers to conditions involving only the heart muscle that are often idiopathic (of unknown cause) or genetic. They primarily affect the myocardium without the involvement of other systemic...
488
Cardiomyopathy IV: Restrictive Cardiomyopathy01:29

Cardiomyopathy IV: Restrictive Cardiomyopathy

438
Restrictive cardiomyopathy (RCM) is a rare heart muscle disease characterized by impaired ventricular filling due to stiffened ventricular walls, leading to significant diastolic dysfunction.EtiologyRestrictive cardiomyopathy can arise from both inherited and acquired diseases, many of which are systemic. It is categorized into four main types: infiltrative, storage, non-infiltrative, and endomyocardial diseases.Infiltrative diseases, such as amyloidosis, lead to RCM by depositing amyloid...
438
Cardiomyopathy V: Interprofessional Care01:29

Cardiomyopathy V: Interprofessional Care

323
Managing cardiomyopathy involves addressing underlying or precipitating causes, treating heart failure with medications, and implementing dietary changes and a balanced exercise and rest regimen.Lifestyle ModificationsCardiomyopathy patients should adopt a low-sodium diet to reduce fluid retention and manage heart failure. A personalized exercise and rest plan helps maintain physical fitness without overstraining the heart. Avoiding alcohol and tobacco is essential to prevent further damage to...
323
Cardiomyopathy II: Dilated Cardiomyopathy01:30

Cardiomyopathy II: Dilated Cardiomyopathy

451
Dilated cardiomyopathy, or DCM, is a progressive myocardial disorder characterized by ventricular chamber dilation and contractile dysfunction.EtiologyVarious factors can cause DCM, including hypertension and heavy alcohol intake, which contribute to the weakening and enlargement of the heart muscle. Viral infections, such as Coxsackievirus B, adenoviruses, and influenza, can lead to DCM by causing inflammation and damage to heart tissue. Certain chemotherapeutic agents, including daunorubicin,...
451

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Related Experiment Video

Updated: Jan 11, 2026

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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ALPK3 Cardiomyopathy: Integrative Review With Systematic Variant Curation, Mechanisms, and Translation.

Chien-Wei Chang1,2, Li Wang1, Zeyu Chen1

  • 1Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego (C.-W.C., L.W., Z.C., J.B., J.C.).

Circulation. Genomic and Precision Medicine
|November 12, 2025
PubMed
Summary
This summary is machine-generated.

Pathogenic variants in ALPK3 cause severe cardiomyopathy. Biallelic loss-of-function leads to early-onset disease, while heterozygous variants cause hypertrophic cardiomyopathy. Gene replacement and drug therapies show promise for ALPK3 cardiomyopathy.

Keywords:
cardiomyopathiesgenetic therapyheart failureprotein kinasessarcomeres

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Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Medicine

Background:

  • Pathogenic variants in ALPK3 (alpha-protein kinase 3) are linked to cardiomyopathy.
  • ALPK3 functions as a sarcomeric M-band scaffold protein, crucial for sarcomere stability and proteostasis.
  • Disease severity correlates with zygosity of ALPK3 variants.

Purpose of the Study:

  • To comprehensively review and curate clinical and experimental data on ALPK3 variants and cardiomyopathy.
  • To elucidate the molecular mechanisms underlying ALPK3-associated cardiomyopathy.
  • To evaluate therapeutic strategies for ALPK3 cardiomyopathy.

Main Methods:

  • Systematic curation of peer-reviewed reports and patient-level data up to June 9, 2025.
  • Analysis of preclinical models, including human induced pluripotent stem cell-derived cardiomyocytes and mouse models.
  • Review of therapeutic interventions, including pharmacological agents and gene replacement therapy.

Main Results:

  • Biallelic loss-of-function ALPK3 variants cause severe, often lethal, early-onset cardiomyopathy with extracardiac manifestations.
  • Heterozygous protein-truncating ALPK3 variants account for 1-4% of adult hypertrophic cardiomyopathy cases, often with specific hypertrophic patterns and fibrosis.
  • Loss of ALPK3 scaffolding function leads to MYOM displacement, thick-filament aggregation, and contractile dysfunction.
  • Therapeutic proof-of-concept demonstrated with mavacamten (myosin inhibitor) and miniALPK3 gene replacement in mouse models.

Conclusions:

  • ALPK3 cardiomyopathy is a significant genetic disorder with distinct clinical presentations based on zygosity.
  • The molecular mechanism involves disruption of sarcomeric proteostasis due to loss of ALPK3 scaffolding function.
  • ALPK3 cardiomyopathy is a viable target for precision medicine, with gene replacement and targeted therapies offering potential disease-modifying treatments.