| Autor: |
Hogarth KA; Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada., Costford SR; Division of Genetics and Genome Biology, SickKids Research Institute, 686 Bay Street, Toronto, M5G 0A4, Canada., Yoon G; Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada., Sondheimer N; Division of Genetics and Genome Biology, SickKids Research Institute, 686 Bay Street, Toronto, M5G 0A4, Canada.; Department of Paediatrics, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada., Maynes JT; Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Canada. jason.maynes@sickkids.ca.; Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Canada. jason.maynes@sickkids.ca. |
| Abstrakt: |
Mitochondria play vital roles in brain development and neuronal activity, and mitochondrial dynamics (fission and fusion) maintain organelle function through the removal of damaged components. Dynamin-like protein-1 (DRP-1), encoded by DNM1L, is an evolutionarily conserved GTPase that mediates mitochondrial fission by surrounding the scission site in concentric ring-like structures via self-oligomerization, followed by GTPase-dependant constriction. Here, we describe the clinical characteristics and cellular phenotype of a patient with severe neurological dysfunction, possessing a homozygous DNM1L variant c.305C>T (p.T115M) in the GTPase domain. For comparative analysis, we also describe a previously identified heterozygous variant demonstrating a rapidly fatal neurocognitive phenotype (c.261dup/c.385:386del, p.W88M*9/E129K*6). Using patient-generated fibroblasts, we demonstrated both DNM1L variants undergo adverse alterations to mitochondrial structure and function, including impaired mitochondrial fission, reduced membrane potential, and lower oxidative capacity including an increased cellular level of reactive oxygen species (ROS) and dsDNA breaks. Mutation of DNM1L was also associated with impaired responses to oxidative stress, as treatment with hydrogen peroxide dramatically increased cellular ROS, with minimal exacerbation of already impaired mitochondrial function. Taken together, our observations indicate that homozygous p.T115M variant of DNM1L produces a neurological and neurodevelopmental phenotype, consistent with impaired mitochondrial architecture and function, through a diminished ability to oligomerize, which was most prevalent under oxidative stress. |
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