ArticleHuman molecular genetics2015
PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 71 citations in OpenAlex.
- Clinical and Genetic Characteristics of Hereditary Arrhythmias and Cardiomyopathies in the Middle East.Mayo Clinic proceedings. Innovations, quality & outcomes · 2026Review
- Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure.Journal of cardiovascular translational research · 2026Review
- Cardiomyocyte programmed cell death in dilated cardiomyopathy: molecular crosstalk and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Programmed ribosomal frameshifting duringScience advances · 2025Article
- Discovery ofDiagnostics (Basel, Switzerland) · 2025Article
- Programmed Cell Death in Heart Failure: Mechanisms, Impacts, and Therapeutic Prospects.Reviews in cardiovascular medicine · 2025Review
- Transcending Age Barriers: Successful Management of Pediatric Dilated Cardiomyopathy with Rare PLEKHM2 Mutation in an Adult Hospital.JACC. Case reports · 2025Article
- Review
- Regulatory mechanisms of mAmerican journal of translational research · 2025Review
- Unraveling mitochondrial crosstalk: a new frontier in heart failure pathogenesis.Frontiers in cardiovascular medicine · 2025Review
- Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review.International journal of molecular sciences · 2024Review
- Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts.Scientific reports · 2024Article
- PLEKHM2 deficiency induces impaired mitochondrial clearance and elevated ROS levels in human iPSC-derived cardiomyocytes.Cell death discovery · 2024Article
- Control of NADThe EMBO journal · 2024Article
- Identification of a novel aromatic-turmerone analog that activates chaperone-mediated autophagy through the persistent activation of p38.Frontiers in cell and developmental biology · 2024Article
- Regulated cell death pathways in cardiomyopathy.Acta pharmacologica Sinica · 2023Review
- Functional defects in hiPSCs-derived cardiomyocytes from patients with a PLEKHM2-mutation associated with dilated cardiomyopathy and left ventricular non-compaction.Biological research · 2023Article
- A Novel Mutation in theInternational journal of molecular sciences · 2023Article
- Novel Susceptibility Genes Drive Familial Non-Medullary Thyroid Cancer in a Large Consanguineous Kindred.International journal of molecular sciences · 2023Article
- hiPSC-Derived Cells as Models for Drug Discovery 2.0.International journal of molecular sciences · 2023Article
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Authors and funding
10 authors at 3 institutions in 3 countries.
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Abstract
Gene mutations, mostly segregating with a dominant mode of inheritance, are important causes of dilated cardiomyopathy (DCM), a disease characterized by enlarged ventricular dimensions, impaired cardiac function, heart failure and high risk of death. Another myocardial abnormality often linked to gene mutations is left ventricular noncompaction (LVNC) characterized by a typical diffuse spongy appearance of the left ventricle. Here, we describe a large Bedouin family presenting with a severe recessive DCM and LVNC. Homozygosity mapping and exome sequencing identified a single gene variant that segregated as expected and was neither reported in databases nor in Bedouin population controls. The PLEKHM2 cDNA2156_2157delAG variant causes the frameshift p.Lys645AlafsTer12 and/or the skipping of exon 11 that results in deletion of 30 highly conserved amino acids. PLEKHM2 is known to interact with several Rabs and with kinesin-1, affecting endosomal trafficking. Accordingly, patients' primary fibroblasts exhibited abnormal subcellular distribution of endosomes marked by Rab5, Rab7 and Rab9, as well as the Golgi apparatus. In addition, lysosomes appeared to be concentrated in the perinuclear region, and autophagy flux was impaired. Transfection of wild-type PLEKHM2 cDNA into patient's fibroblasts corrected the subcellular distribution of the lysosomes, supporting the causal effect of PLEKHM2 mutation. PLEKHM2 joins LAMP-2 and BAG3 as a disease gene altering autophagy resulting in an isolated cardiac phenotype. The association of PLEKHM2 mutation with DCM and LVNC supports the importance of autophagy for normal cardiac function.
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