De novo missense variant in the GTPase effector domain (GED) of DNM1L leads to static encephalopathy and seizures

Abstract

DNM1L encodes a GTPase of the dynamin superfamily, which plays a crucial role in mitochondrial and peroxisomal fission. Pathogenic variants affecting the middle domain and the GTPase domain of DNM1L have been implicated in encephalopathy because of defective mitochondrial and peroxisomal fission 1 (EMPF1, MIM #614388). Patients show variable phenotypes ranging from severe hypotonia leading to death in the neonatal period to developmental delay/regression, with or without seizures. Familial pathogenic variants in the GTPase domain have also been associated with isolated optic atrophy. We present a 27-yr-old woman with static encephalopathy, a history of seizures, and nystagmus, in whom a novel de novo heterozygous variant was detected in the GTPase effector domain (GED) of DNM1L (c.2072A>G, p.Tyr691Cys). Functional studies in Drosophila demonstrate large, abnormally distributed peroxisomes and mitochondria, an effect very similar to that of middle domain missense alleles observed in pediatric subjects with EMPF1. To our knowledge, not only is this the first report of a disease-causing variant in the GED domain in humans, but this is also the oldest living individual reported with EMPF1. Longitudinal data of this kind helps to expand our knowledge of the natural history of a growing list of DNM1L -related disorders.

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

“…Since the first report of a pathogenic variant in DNM1L [ 19 ], several pathogenic variants in DRP1 have been associated with highly variable neurological phenotypes [ 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 ], with some resulting in complex phenotypes and early mortality [ 19 , 228 , 229 , 230 , 231 ]. Meanwhile, a murine model harboring a mutation in DNM1L leads to cardiomyopathy [ 232 ], a common type of organ dysfunction in complex mitochondrial syndromes [ 233 ].…”

Dynamic properties of mitochondria during human corticogenesis

“…In fact, mitochondrial diseases, which are linked to mutations that impair OXPHOS, affect about 1 in 5000 live births ( Schaefer et al, 2004 ). In addition, perturbations in genes involved in the maintenance of mitochondrial morphology and cristae dynamics also have devastating effects on human brain development ( Table 1 ) ( Amati-Bonneau et al, 2008 ; Assia Batzir et al, 2019 ; Bartsakoulia et al, 2018 ; Benincá et al, 2020 ; Fahrner et al, 2016 ; Gerber et al, 2017 ; Gödiker et al, 2018 ; Hogarth et al, 2018 ; Koch et al, 2016 ; Ladds et al, 2018 ; Mei et al, 2019 ; Nasca et al, 2018 ; Panda et al, 2020 ; Ryan et al, 2018 ; Schmid et al, 2019 ; Shamseldin et al, 2012 ; Sheffer et al, 2016 ; Shimizu et al, 2003 ; Tarailo-Graovac et al, 2019 ; Vanstone et al, 2016 ; Verrigni et al, 2019 ; von Spiczak et al, 2017 ; Waterham et al, 2007 ; Whitley et al, 2018 ; Zeharia et al, 2016 ). Although animal models have been pivotal for elucidating some phenotypes associated with dysfunctional mitochondria, human psychiatric and neurological conditions have developmental origins that cannot be fully understood using animal models ( Molnár et al, 2019 ; O'Rahilly and Müller, 2008 ).…”

“…Mitochondrial homeostasis is maintained through the concerted execution of mitochondrial dynamics (fusion and fission), cristae dynamics, motility and mitophagy ( Barnhart, 2016 ; Chen and Dorn, 2013 ; Cogliati et al, 2013 ; Frank et al, 2001 ; Giacomello et al, 2020 ; Schwarz, 2013 ; Scorrano et al, 2002 ; Ziviani et al, 2010 ). As evidence of the importance of these dynamic properties in the modulation of brain development, rare mutations in proteins involved in their regulation cause phenotypically heterogeneous and severe neurodevelopmental diseases ( Table 1 ) ( Amati-Bonneau et al, 2008 ; Assia Batzir et al, 2019 ; Bartsakoulia et al, 2018 ; Benincá et al, 2020 ; Fahrner et al, 2016 ; Gerber et al, 2017 ; Gödiker et al, 2018 ; Hogarth et al, 2018 ; Koch et al, 2016 ; Ladds et al, 2018 ; Mei et al, 2019 ; Nasca et al, 2018 ; Panda et al, 2020 ; Ryan et al, 2018 ; Schmid et al, 2019 ; Shamseldin et al, 2012 ; Sheffer et al, 2016 ; Shimizu et al, 2003 ; Tarailo-Graovac et al, 2019 ; Vanstone et al, 2016 ; Verrigni et al, 2019 ; von Spiczak et al, 2017 ; Waterham et al, 2007 ; Whitley et al, 2018 ; Zeharia et al, 2016 ). Emerging studies have highlighted the crosstalk between the mitochondrial dynamics machinery, the mitochondrial contact site and the cristae organizing system (MICOS), as well as motility and mitophagy machinery at the mitochondria ( Kageyama et al, 2014 ; Morciano et al, 2016 ; Fu et al, 2019 ; Picard et al, 2016 ).…”

Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

“…The patient is a 27-year-old girl with a history of neonatal hypotonia progressed to spasticity, developmental delays, and static encephalopathy. Functional studies in Drosophila suggest a dominant-negative mechanism effect of this variant, due to the mutation failed to rescue Drosophila drp1 lethality and caused an altered peroxisomal phenotype [129].…”