PLEKHM2 – Dilated Cardiomyopathy

PLEKHM2 mutations cause autosomal recessive dilated cardiomyopathy characterized by ventricular enlargement, systolic dysfunction, and frequently left ventricular noncompaction. A homozygous frameshift variant c.1932_1933del (p.Lys645fs) segregates with disease in a large consanguineous Bedouin kindred (PMID:26464484). A second unrelated pediatric DCM case carrying a rare PLEKHM2 mutation further supports an autosomal recessive inheritance (PMID:40054934). Functional studies in patient fibroblasts reveal abnormal Rab5/7/9-marked endosomal distribution, perinuclear lysosomal clustering and impaired autophagic flux, all rescued by wild-type PLEKHM2 cDNA (PMID:26464484). In PLEKHM2-KO hiPSC-derived cardiomyocytes, contractility and calcium handling are compromised, damaged mitochondria accumulate with elevated ROS and decreased membrane potential; WT overexpression restores autophagy and contractile function (PMID:38490981). These findings provide moderate functional support for PLEKHM2 deficiency in DCM pathogenesis. Further studies are warranted to expand the variant spectrum and define genotype–phenotype correlations.

Key Take-home: PLEKHM2 should be included in genetic testing panels for early‐onset recessive dilated cardiomyopathy with LVNC, enabling functional diagnostics and potential targeted interventions.

References

• Human molecular genetics • 2015 • PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction. PMID:26464484
• Cell death discovery • 2024 • PLEKHM2 deficiency induces impaired mitochondrial clearance and elevated ROS levels in human iPSC-derived cardiomyocytes. PMID:38490981
• JACC Case Reports • 2025 • Transcending Age Barriers: Successful Management of Pediatric Dilated Cardiomyopathy with Rare PLEKHM2 Mutation in an Adult Hospital. PMID:40054934

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