A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism

Parthasarathy, Shridhar; Ruggiero, Sarah M; Gélot, A.; Soardi, Fernanda Caroline; Ribeiro, Bethânia F R; Pires, Douglas E. V.; Ascher, David B.; Schmitt, Alain; Rambaud, Caroline; Represa, Alfonso; Xie, Hongbo; Lusk, Laina; Wilmarth, Olivia; McDonnell, Pamela Pojomovsky; Juarez, Olivia A; Grace, Alexandra N; Buratti, Julien; Mignot, Cyril; Gras, Domitille; Nava, Caroline; Pierce, Samuel R.; Keren, Boris; Kennedy, Benjamin C.; Pena, Sérgio D.J.; Helbig, Ingo; Cuddapah, Vishnu Anand

doi:10.1016/j.ajhg.2022.11.002

Cited by 19 publications

(16 citation statements)

References 49 publications

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“…In particular, the splicing site that involves exons 10 and 11 has been described also in mice and human orthologs. Notably, mutations in these alternative spliced exons have been linked to the developmental and epileptic encephalopathy (DEE) disease in mammals, with more severe phenotype depending on the spliced exon carrying the mutations (Allen et al, 2016; Asinof et al, 2016; Boumil et al, 2010; Griffin et al, 2021; Kolnikova et al, 2018; Parthasarathy et al, 2022; Sahly et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Bragato

Pistocchi

Bellipanni

et al. 2023

J of Neuroscience Research

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Classical dynamins (DNMs) are GTPase proteins engaged in endocytosis, a fundamental process for cargo internalization from the plasma membrane. In mammals, three DNM genes are present with different expression patterns. DNM1 is expressed at high levels in neurons, where it takes place in the recycling of synaptic vesicles; DNM2 is ubiquitously expressed, while DNM3 is found in the brain and in the testis. Due to the conservation of genes in comparison to mammals, we took advantage of a zebrafish model for functional characterization of dnm1a, ortholog of mammalian DNM1. Our data strongly demonstrated that dnm1a has a nervous tissue-specific expression pattern and plays a role in the formation of both axon and synapse. This is the first in vivo study that collects evidence about the effects of dnm1a loss of function in zebrafish, thus providing a new excellent model to be used in different scientific fields.

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Section: Discussionmentioning

confidence: 99%

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Bragato

Pistocchi

Bellipanni

et al. 2023

J of Neuroscience Research

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“…4 To the best of our knowledge, eight cases, including our case, have been reported with white matter abnormalities such as delayed myelination or hypomyelination. 2,[5][6][7][8][9] While two cases with GTPase-domain mutations show white matter abnormalities, 2,5 six cases with middle-domain mutations have been reported, [5][6][7][8][9] suggesting a relationship between the site of gene mutation and the presence of white matter abnormalities. However, there were cases of GTPase-and middle-domain pathogenic variants without delayed myelination, suggesting the presence of factors other than the mutated region.…”

Section: Discussionmentioning

confidence: 99%

Abnormal axonal development and severe epileptic phenotype in Dynamin‐1 (DNM1) encephalopathy

Matsubara,

Kuki,

Ishioka

et al. 2023

Epileptic Disorders

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Dynamin‐1 (DNM1) is involved in synaptic vesicle recycling, and DNM1 mutations can lead to developmental and epileptic encephalopathy. The neuroimaging of DNM1 encephalopathy has not been reported in detail. We describe a severe phenotype of DNM1 encephalopathy showing characteristic neuroradiological features. In addition, we reviewed previously reported cases who have DNM1 pathogenic variants with white matter abnormalities. Our case presented drug‐resistant seizures from 1 month of age and epileptic spasms at 2 years of age. Brain MRI showed no progression of myelination, progression of diffuse cerebral atrophy, and a thin corpus callosum. Proton magnetic resonance spectroscopy showed a decreased N‐acetylaspartate peak and diffusion tensor imaging presented with less pyramidal decussation. Whole‐exome sequencing revealed a recurrent de novo heterozygous variant of DNM1. So far, more than 50 cases of DNM1 encephalopathy have been reported. Among these patients, delayed myelination occurred in two cases of GTPase‐domain DNM1 encephalopathy and in six cases of middle‐domain DNM1 encephalopathy. The neuroimaging findings in this case suggest inadequate axonal development. DNM1 is involved in the release of synaptic vesicles with the inhibitory transmitter GABA, suggesting that GABAergic neuron dysfunction is the mechanism of refractory epilepsy in DNM1 encephalopathy. GABA‐mediated signaling mechanisms play important roles in axonal development and GABAergic neuron dysfunction may be cause of white matter abnormalities in DNM1 encephalopathy.

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“…DNM1 -related disorder, a severe DEE characterized by profound hypotonia, highly abnormal hypssarrythmic EEGs, West syndrome evolving to Lennox-Gastaut syndrome and severe to profound developmental delays, was first identified to be caused by missense gain-of-function variants within the ATPase and middle domains of the protein, interfering with the protein's ability to heterodimerize and aid in vesicle recycling [35]. Recently, the most recurrent described variant in DNM1 was identified, an apparent splice variant (c.1197-8G>A) in the canonical isoform of the protein, but one that actually acts as a nonapparent missense variant in the isoform of the protein most highly expressed in the paediatric brain [36 ▪ ]. In addition, genetic causes first characterized as operating through dominant negative or loss-of-function mechanisms have had novel variants identified that are proven to operate in a gain-of-function manner, resulting in novel presentations and phenotypes.…”

Section: Novel Presentations Of Known Genesmentioning

confidence: 99%

The current landscape of epilepsy genetics: where are we, and where are we going?

Ruggiero

Xian

Helbig

2023

Current Opinion in Neurology

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Purpose of reviewIn this review, we aim to analyse the progress in understanding the genetic basis of the epilepsies, as well as ongoing efforts to define the increasingly diverse and novel presentations, phenotypes and divergences from the expected that have continually characterized the field.Recent findingsA genetic workup is now considered to be standard of care for individuals with an unexplained epilepsy, due to mounting evidence that genetic diagnoses significantly influence treatment choices, prognostication, community support, and increasingly, access to clinical trials. As more individuals with epilepsy are tested, novel presentations of known epilepsy genes are being discovered, and more individuals with self-limited epilepsy are able to attain genetic diagnoses. In addition, new genes causative of epilepsy are being uncovered through both traditional and novel methods, including large international data-sharing collaborations and massive sequencing efforts as well as computational methods and analyses driven by the Human Phenotype Ontology (HPO).SummaryNew approaches to gene discovery and characterization are advancing rapidly our understanding of the genetic and phenotypic architecture of the epilepsies. This review highlights relevant and groundbreaking studies published recently that have pushed forward the field of epilepsy genetics.

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A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism

Cited by 19 publications

References 49 publications

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Zebrafish dnm1a gene plays a role in the formation of axons and synapses in the nervous tissue

Abnormal axonal development and severe epileptic phenotype in Dynamin‐1 (DNM1) encephalopathy

The current landscape of epilepsy genetics: where are we, and where are we going?

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