The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathyResearch in context
Walaa Almutawa,
Christopher Smith,
Rasha Sabouny,
Ryan B. Smit,
Tian Zhao,
Rachel Wong,
Laurie Lee-Glover,
Justine Desrochers-Goyette,
Hema Saranya Ilamathi,
Oksana Suchowersky,
Marc Germain,
Paul E. Mains,
Jillian S. Parboosingh,
Gerald Pfeffer,
A. Micheil Innes,
Timothy E. Shutt
Affiliations
Walaa Almutawa
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Christopher Smith
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Rasha Sabouny
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Ryan B. Smit
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Tian Zhao
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Rachel Wong
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Laurie Lee-Glover
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Justine Desrochers-Goyette
Groupe de Recherche en Signalisation Cellulaire and Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada; Centre de Recherche Biomed, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
Hema Saranya Ilamathi
Groupe de Recherche en Signalisation Cellulaire and Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada; Centre de Recherche Biomed, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
Oksana Suchowersky
Departments of Medicine (Neurology), Medical Genetics and Pediatrics, University of Alberta, Edmonton, AB, Canada
Marc Germain
Groupe de Recherche en Signalisation Cellulaire and Département de Biologie Médicale, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada; Centre de Recherche Biomed, Université du Québec à Trois-Rivières, Trois-Rivières, QC, Canada
Paul E. Mains
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Jillian S. Parboosingh
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Gerald Pfeffer
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
A. Micheil Innes
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Corresponding authors at: Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Timothy E. Shutt
Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Hotchkiss Brain Institute, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada; Corresponding authors at: Alberta Children's Hospital Research Institute, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Background: Peripheral neuropathies are often caused by disruption of genes responsible for myelination or axonal transport. In particular, impairment in mitochondrial fission and fusion are known causes of peripheral neuropathies. However, the causal mechanisms for peripheral neuropathy gene mutations are not always known. While loss of function mutations in MYH14 typically cause non-syndromic hearing loss, the recently described R941L mutation in MYH14, encoding the non-muscle myosin protein isoform NMIIC, leads to a complex clinical presentation with an unexplained peripheral neuropathy phenotype. Methods: Confocal microscopy was used to examine mitochondrial dynamics in MYH14 patient fibroblast cells, as well as U2OS and M17 cells overexpressing NMIIC. The consequence of the R941L mutation on myosin activity was modeled in C. elegans. Findings: We describe the third family carrying the R941L mutation in MYH14, and demonstrate that the R941L mutation impairs non-muscle myosin protein function. To better understand the molecular basis of the peripheral neuropathy phenotype associated with the R941L mutation, which has been hindered by the fact that NMIIC is largely uncharacterized, we have established a previously unrecognized biological role for NMIIC in mediating mitochondrial fission in human cells. Notably, the R941L mutation acts in a dominant-negative fashion to inhibit mitochondrial fission, especially in the cell periphery. In addition, we observed alterations to the organization of the mitochondrial genome. Interpretation: As impairments in mitochondrial fission cause peripheral neuropathy, this insight into the function of NMIIC likely explains the peripheral neuropathy phenotype associated with the R941L mutation. Fund: This study was supported by the Alberta Children's Hospital Research Institute, the Canadian Institutes of Health Research and the Care4Rare Canada Consortium. Keywords: Mitochondria, Mitochondrial fission, Peripheral neuropathy, Non-muscle myosin, mtDNA, Caenorhabditis elegans
