Investigating mitochondrial dynamic change caused by domain-specific missense mutations in DNM1L associated with a varying degree of neurological phenotypes in patients

Abstract

Mitochondrial dynamics, including mitochondrial fission and fusion, plays an essential role in neurodevelopment. DNM1L encodes a dynaminrelated GTPase which functions in mitochondrial and peroxisomal fission. Pathogenic mutations affecting different domains of DNM1L are associated with a wide range of neurological phenotypes from relatively mild optic atrophy to neonatal lethality. However, the underlying molecular mechanisms of genotypephenotype correlation is not well studied. we primarily observed cellular and developmental phenotypes by overexpressing representative DNM1L variants from GTPase and middle domains. We aim to investigate the neurodevelopmental function of DNM1L variants via a combination of Tet-OFF system and CRISPR/Cas9 knockout techniques in embryonic stem cells. Our work may help to expand the comprehension of DNM1L-related diseases thus to develop targeted therapy.