Lethal Disorder of Mitochondrial Fission Caused by Mutations in DNM1L

Yoon, Grace; Malam, Zeenat; Paton, Tara; Marshall, Christian R.; Hyatt, Ella; Ivakine, Evgueni A.; Scherer, Stephen W.; Lee, Kyong-Soon; Hawkins, Cynthia; Cohn, Ronald D.; Boycott, Kym M.; Friedman, Jan M.; Michaud, Jacques L.; Bernier, François; Brudno, Michael; Fernandez, Bridget A.; Knoppers, Bartha Maria; Samuels, Mark E.

doi:10.1016/j.jpeds.2015.12.060

Cited by 68 publications

(55 citation statements)

References 20 publications

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“…In contrast to the de novo, lethal, infantile-onset phenotype reported by Waterham et al 10 and the sibling pair with recessive changes referred to in the unpublished abstract by Yoon et al, 11 our proband presented with prolonged survival and a relatively nonspecific refractory epilepsy, with few clinical signs suggestive of a mitochondrial and/or peroxisomal disorder. Given the obvious difficulties inherent to the clinical recognition of this disorder, the most practical route to diagnosis is An immediately adjacent glycine-to-aspartate substitution, p.Gly363Asp, has been studied extensively in vitro, and this change appears to permit (normal) DNM1L tetramerization in the cytoplasm while abolishing higher-order self-assembly and polymerization-dependent GTPase activity.…”

Section: Discussioncontrasting

confidence: 84%

“…The clinical course was severe, with survival of 37 days. The sole other mention in the literature of this condition is a meeting abstract by Yoon et al 11 regarding a sibling pair with encephalopathy, hepatic dysfunction, giant intraneuronal mitochondria, and neonatal lethality, with compound heterozygous DNM1L changes consistent with recessive inheritance. Here, we describe a child with a comparatively indolent phenotype comprising epilepsy, developmental delay, normal mitochondrial and peroxisomal screening tests, and prolonged survival.…”

Section: Introductionmentioning

confidence: 99%

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DNM1L-related mitochondrial fission defect presenting as refractory epilepsy

et al. 2015

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Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G4A; NP_036192.2:p. (Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.

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Section: Discussioncontrasting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

DNM1L-related mitochondrial fission defect presenting as refractory epilepsy

et al. 2015

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“…Mutations in DRP1 result in clinical phenotypes with a strong neurological component, ranging from microcephaly with multi-organ failure and neonatal lethality to intractable epilepsy in childhood (Fahrner et al, 2016; Nasca et al, 2016; Sheffer et al, 2016; Vanstone et al, 2016; Waterham et al, 2007; Yoon et al, 2016). Homozygous mutations in MFF result in severe neuromuscular disease (Koch et al, 2016; Shamseldin et al, 2012).…”

Section: Mitochondrial Fusion and Fissionmentioning

confidence: 99%

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

2017

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Cancer and stem cells appear to share a common metabolic profile that is characterized by high utilization of glucose through aerobic glycolysis. In the presence of sufficient nutrients, this metabolic strategy provides sufficient cellular ATP while additionally providing important metabolites necessary for the biosynthetic demands of continuous cell proliferation. Recent studies indicate that this metabolic profile is dependent on genes that regulate the fusion and fission of mitochondria. High levels of mitochondrial fission activity are associated with high proliferation and invasiveness in some cancer cells and with self-renewal and resistance to differentiation in some stem cells. These observations reveal new ways in which mitochondria regulate cell physiology, through their effects on metabolism and cell signaling.

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“…The first identified mutation was neonatal lethal and resulted in large-scale brain malformations (Waterham et al 2007). More recently identified de novo mutations in Dnm1l presented later in childhood as encephalopathy, seizures, and impaired nociception (Fahrner et al 2016, Nasca et al 2016, Sheffer et al 2016, Vanstone et al 2016, Yoon et al 2016). All mutations reported so far are dominant-negative, interfering with oligomerization, mitochondrial fission activity, and mitochondrial recruitment of Drp1, to an extent inversely related to age of symptom onset.…”

Section: Mitochondrial Dynamics In Nervous System Developmentmentioning

confidence: 99%

An emerging role for mitochondrial dynamics in schizophrenia

Flippo

Strack

2017

Schizophrenia Research

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Abnormal brain development has long been thought to contribute to the pathophysiology of schizophrenia. Impaired dendritic arborization, synaptogenesis, and long term potentiation and memory have been demonstrated in animal models of schizophrenia. In addition to aberrant nervous system development, altered brain metabolism and mitochondrial function has long been observed in schizophrenic patients. Single nucleotide polymorphisms in the mitochondrial genome as well as impaired mitochondrial function have both been associated with increased risk for developing schizophrenia. Mitochondrial function in neurons is highly dependent on fission, fusion, and transport of the organelle, collectively referred to as mitochondrial dynamics. Indeed, there is mounting evidence that mitochondrial dynamics strongly influences neuron development and synaptic transmission. While there are a few studies describing altered mitochondrial shape in schizophrenic patients, as well as in animal and in vitro models of schizophrenia, the precise role of mitochondrial dynamics in the pathophysiology of schizophrenia is all but unexplored. Here we discuss the influence of mitochondrial dynamics and mitochondrial function on nervous system development, and highlight recent work suggesting a link between aberrant mitochondrial dynamics and schizophrenia.

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Lethal Disorder of Mitochondrial Fission Caused by Mutations in DNM1L

Cited by 68 publications

References 20 publications

DNM1L-related mitochondrial fission defect presenting as refractory epilepsy

DNM1L-related mitochondrial fission defect presenting as refractory epilepsy

Mitochondrial Dynamics in Regulating the Unique Phenotypes of Cancer and Stem Cells

An emerging role for mitochondrial dynamics in schizophrenia

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