A novel de novo dominant negative mutation in DNM1L impairs mitochondrial fission and presents as childhood epileptic encephalopathy

Abstract

DNM1L encodes dynamin-related protein (DRP1/ DLP1), a key component of the mitochondrial fission machinery that is essential to proper functioning of the mammalian brain. Two previously reported probands with de novo missense mutations in DNM1L presented in the first year of life with severe encephalopathy and refractory epilepsy, one with death at 37 days after birth. In contrast, we report identical novel missense mutations in DNM1L in two unrelated probands who experienced normal development for several years before presenting with refractory focal status epilepticus and subsequent rapid neurological decline. We expand the phenotype of DNM1L-related mitochondrial fission defects, reveal common unique clinical characteristics and imaging findings, and compare the cellular impact of this novel mutation to the previously reported A395D lethal variant. We demonstrate that our R403C mutation acts by a dominant-negative mechanism and reduces oligomerization, mitochondrial fission activity, and mitochondrial recruitment of DRP1, but to a lesser extent compared to the A395D mutation. In contrast to the initial report of neonatal lethality resulting from DNM1L mutation and DRP1 dysfunction, our results show that milder DRP1 impairment is compatible with normal early development and subsequently results in a distinct set of neurological findings. In addition, we identify a common pathogenic mechanism whereby DNM1L mutations impair mitochondrial fission.

Mitochondrial diseases and status epilepticus

“…46,47 An additional possibility is that an immunemediated component of mitochondrial epilepsy drives continuing seizure activity. 35 Recent studies in animal models also support a role for disordered mitochondrial dynamics in the pathophysiology of status epilepticus. Folatereceptor blocking autoantibodies and oligoclonal bands have been observed in the cerebrospinal fluid of patients with POLG mutations, and one case had neuropathologic evidence of an autoimmune disease process resembling acute disseminated encephalomyelitis.…”

“…35 Mutations of the JAK-STAT cytokine STAT2 also caused intractable epilepsy associated with defective mitochondrial fission. It is therefore unsurprising that several defects of mitochondrial dynamics have been linked to status epilepticus, including DNM1L mutations encoding the mitochondrial fission protein DRP1.…”

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

“…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).…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Similarly, although ADOA is clinically characterized by degeneration of the optic nerve, ∼20% of patients present with extraocular phenotypes, such as peripheral neuropathy and sensorineural hearing loss (Lenaers et al, 2012). Although very rare, de novo hypomorphic mutations in DNM1L, the gene encoding Drp1, are equally devastating and can cause severely impaired development of the nervous system, which leads to epileptic encephalopathy, development delay, pain insensitivity and evendepending on the mutation -early postnatal death (Fahrner et al, 2016;Sheffer et al, 2016;Waterham et al, 2007).…”