title: PLEKHM2 mutation leads to abnormal localization of lysosomes, impaired autophagy flux and associates with recessive dilated cardiomyopathy and left ventricular noncompaction.
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.
authors.affiliation: Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Emad
authors.initials: E
authors.lastname: Muhammad
authors.affiliation: Department of Pediatric Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84101, Israel.
authors.forename: Aviva
authors.initials: A
authors.lastname: Levitas
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany.
authors.forename: Sonia R
authors.initials: SR
authors.lastname: Singh
authors.affiliation: Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Alex
authors.initials: A
authors.lastname: Braiman
authors.affiliation: Regenerative Medicine and Stem Cell Research Center, Beer-Sheva 84105, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Ofir
authors.affiliation: Regenerative Medicine and Stem Cell Research Center, Beer-Sheva 84105, Israel.
authors.forename: Sharon
authors.initials: S
authors.lastname: Etzion
authors.affiliation: Department of Pediatrics, Division of Medical Genetics and Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
authors.affiliation: Regenerative Medicine and Stem Cell Research Center, Beer-Sheva 84105, Israel, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel and.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Etzion
authors.affiliation: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany, DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.affiliation: Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel ruthi@bgu.ac.il.
authors.forename: Ruti
authors.initials: R
authors.lastname: Parvari
mesh_terms: D000293:Adolescent; D001343:Autophagy / Q000235:genetics / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins