<i>PLEKHM2</i>
            Loss-of-Function Is Associated With Dilated Cardiomyopathy

Atkins, Jessica; Gensemer, Cortney; Foil, Kimberly; Morningstar, Jordan; Ramos, Hannia; Bakel, Adrian B. Van; Norris, Russell A.; Judge, Daniel P.

doi:10.1161/circgen.121.003594

Cited by 4 publications

(6 citation statements)

References 7 publications

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“…To our knowledge this patient represents the third family with homozygous/compound heterozygous truncation of PLEKHM2 . In previous studies the patients with PLEKHM2 variants presented with DCM and features of LVNC, and a family history of SCD ( 31 , 32 ).…”

Section: Discussionmentioning

confidence: 89%

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Heliö,

Cicerchia,

Hathaway

et al. 2023

Front. Cardiovasc. Med.

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BackgroundFamilial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria.Methods and resultsThis study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23–316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator.ConclusionsPanel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.

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Section: Discussionmentioning

confidence: 89%

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Heliö,

Cicerchia,

Hathaway

et al. 2023

Front. Cardiovasc. Med.

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“…Overall, the absence of Plekhm2 in mice appears to promote compensatory mechanism(s) enabling the heart to manage functionally even in the presence of neurohormonal stress without detrimental consequences. Importantly, while PLEKHM2 loss of function mutations are clearly associated with a DCM phenotype in human 9 , 16 and autophagy derangement in patient's primary fibroblast 9 as well as in iPSC-induced cardiomyocytes 17 , 46 , autophagy derangement could not be identified in murine cardiomyocytes. Whether this overt difference explains the absence of DCM phenotype in the PLK2-KO mice remains to be determined.…”

Section: Discussionmentioning

confidence: 90%

“…In this study we examine the roles of Plekhm2 in the murine heart using PLK2-KO mice and cultured primary cardiac cells with ablated Plekhm2 expression. The main motivation for our study steams from the fact that PLEKHM2 loss-of-function mutations were associated with early onset DCM in two independent studies 9 , 16 , as well as abnormal lysosomal localization and impaired autophagy in the fibroblasts of an inflicted indivisual 9 . Our main findings indicate that murine Plekhm2 is essential for normal cardiac autophagy following nutrient deprivation and aging.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, in that report, we showed that the patient’s primary fibroblasts exhibited an abnormal subcellular distribution of endosomes and lysosomes and impaired autophagy 9 . Recently, Atkins et al 16 reported a 21-year-old woman with DCM and prominent LV apical trabeculations associated with compound heterozygous loss-of-function variations in the PLEKHM2 gene. They demonstrated an absence of PLEKHM2 protein from the myocardial tissue, supporting our identified association between PLEKHM2 dysfunction and DCM 9 .…”

Section: Introductionmentioning

confidence: 99%

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Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts

Etzion,

Hijaze,

Segal

et al. 2024

Sci Rep

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Plekhm2 is a protein regulating endosomal trafficking and lysosomal distribution. We recently linked a recessive inherited mutation in PLEKHM2 to a familial form of dilated cardiomyopathy and left ventricular non-compaction. These patients’ primary fibroblasts exhibited abnormal lysosomal distribution and autophagy impairment. We therefore hypothesized that loss of PLEKHM2 impairs cardiac function via autophagy derangement. Here, we characterized the roles of Plekhm2 in the heart using global Plekhm2 knockout (PLK2-KO) mice and cultured cardiac cells. Compared to littermate controls (WT), young PLK2-KO mice exhibited no difference in heart function or autophagy markers but demonstrated higher basal AKT phosphorylation. Older PLK2-KO mice had body and heart growth retardation and increased LC3II protein levels. PLK2-KO mice were more vulnerable to fasting and, interestingly, impaired autophagy was noted in vitro, in Plekhm2-deficient cardiofibroblasts but not in cardiomyocytes. PLK2-KO hearts appeared to be less sensitive to pathological hypertrophy induced by angiotensin-II compared to WT. Our findings suggest a role of Plekhm2 in murine cardiac autophagy. Plekhm2 deficiency impaired autophagy in cardiofibroblasts, but the autophagy in cardiomyocytes is not critically dependent on Plekhm2. The absence of Plekhm2 in mice appears to promote compensatory mechanism(s) enabling the heart to manage angiotensin-II-induced stress without detrimental consequences.

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“…RVAS: 1.9% versus 0% ( P < 0.00001) 19 ECG traits – PLEKHM2 Kinesin transport cargo adapter protein DCM 2 (refs. 87 , 88 ) 2 5 PTV Exome (1 trio). Panel (1 trio).…”

Section: Resultsmentioning

confidence: 99%

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Lipov,

Jurgens,

Mazzarotto

et al. 2023

Nat Cardiovasc Res

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Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

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PLEKHM2 Loss-of-Function Is Associated With Dilated Cardiomyopathy

Cited by 4 publications

References 7 publications

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients

Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts

Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

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