scholarly journals Biallelic and de novo variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

2021 ◽  
Author(s):  
Laura C Bott ◽  
Mitra Forouhan ◽  
Maria Lieto ◽  
Ambre Sala ◽  
Ruth Ellerington ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Atp Hydrolysis ◽  
De Novo ◽  
Proton Translocation ◽  
Critical Role ◽  
Epileptic Encephalopathy ◽  
Developmental Defect ◽  
Lysosomal Disease ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy

The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Here we identified 17 individuals from 14 unrelated families with variants in ATP6V0A1, the brain-enriched isoform in the V0 domain. Five affected subjects carried biallelic variants in this gene and presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals were found as de novo cases (missense variants) and showed severe developmental and epileptic encephalopathy. We describe that the disease-associated variants lead to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment. The R740Q mutation, which alone accounts for almost 50% of the variants identified in this cohort, causes autophagic dysfunction and a severe developmental defect in C. elegans. Altogether, our findings establish a novel cause of lysosomal disease and provide a direct link with endolysosomal acidification in the pathophysiology of these conditions.

scholarly journals A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

2014 ◽  
Vol 47 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Mikko Muona ◽  
Samuel F Berkovic ◽  
Leanne M Dibbens ◽  
Karen L Oliver ◽  
Snezana Maljevic ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Progressive Myoclonus Epilepsy ◽  
Myoclonus Epilepsy

A KCNC1 mutation in Epilepsy of Infancy with Focal Migrating Seizures produces functional channels that fail to be regulated by phosphorylation

2021 ◽  
Author(s):  
Yalan Zhang ◽  
Syed R Ali ◽  
Rima Nabbout ◽  
Giulia Barcia ◽  
Leonard K. Kaczmarek
Keyword(s):  
De Novo ◽  
Channel Modulation ◽  
Progressive Myoclonus Epilepsy ◽  
C Terminus ◽  
Myoclonus Epilepsy ◽  
Voltage Dependent ◽  
Genes Encoding ◽  
Clear Change

Channelopathies caused by mutations in genes encoding ion channels generally produce a clear change in channel function. Accordingly, mutations in KCNC1, which encodes the voltage-dependent Kv3.1 potassium channel, result in Progressive Myoclonus Epilepsy as well as other Developmental and Epileptic Encephalopathies, and these have been shown to reduce or fully abolish current amplitude. One exception to this is the mutation A513V Kv3.1b, located in the cytoplasmic C-terminal domain of the channel protein. This de novo variant was detected in a patient with Epilepsy of Infancy with Focal Migrating Seizures (EIFMS) but no difference could be detected between A513V Kv3.1 current and that of wild type Kv3.1. Using both biochemical and electrophysiological approaches, we have now confirmed that this variant produces functional channels but find that the A513V mutation renders the channel completely insensitive to regulation by phosphorylation at S503, a nearby regulatory site in the C-terminus. In this respect, the mutation resembles those in another channel, KCNT1, which are the major cause of EIFMS. Because the amplitude of Kv3.1 current is constantly adjusted by phosphorylation in vivo, our findings suggest that loss of such regulation contributes to EIFMS phenotype and emphasize the role of channel modulation for normal neuronal function.

scholarly journals Analysis of the Structural Mechanism of ATP Inhibition at the AAA1 Subunit of Cytoplasmic Dynein-1 Using a Chemical “Toolkit”

2021 ◽  
Vol 22 (14) ◽  
pp. 7704
Author(s):  
Sayi’Mone Tati ◽  
Laleh Alisaraie
Keyword(s):  
Binding Affinity ◽  
Atp Hydrolysis ◽  
Critical Role ◽  
Motor Protein ◽  
Structural Data ◽  
Retrograde Transport ◽  
Cytoplasmic Dynein ◽  
Motor Domain ◽  
Conformational Search ◽  
Structural Mechanism

Dynein is a ~1.2 MDa cytoskeletal motor protein that carries organelles via retrograde transport in eukaryotic cells. The motor protein belongs to the ATPase family of proteins associated with diverse cellular activities and plays a critical role in transporting cargoes to the minus end of the microtubules. The motor domain of dynein possesses a hexameric head, where ATP hydrolysis occurs. The presented work analyzes the structure–activity relationship (SAR) of dynapyrazole A and B, as well as ciliobrevin A and D, in their various protonated states and their 46 analogues for their binding in the AAA1 subunit, the leading ATP hydrolytic site of the motor domain. This study exploits in silico methods to look at the analogues’ effects on the functionally essential subsites of the motor domain of dynein 1, since no similar experimental structural data are available. Ciliobrevin and its analogues bind to the ATP motifs of the AAA1, namely, the walker-A (W-A) or P-loop, the walker-B (W-B), and the sensor I and II. Ciliobrevin A shows a better binding affinity than its D analogue. Although the double bond in ciliobrevin A and D was expected to decrease the ligand potency, they show a better affinity to the AAA1 binding site than dynapyrazole A and B, lacking the bond. In addition, protonation of the nitrogen atom in ciliobrevin A and D, as well as dynapyrazole A and B, at the N9 site of ciliobrevin and the N7 of the latter increased their binding affinity. Exploring ciliobrevin A geometrical configuration suggests the E isomer has a superior binding profile over the Z due to binding at the critical ATP motifs. Utilizing the refined structure of the motor domain obtained through protein conformational search in this study exhibits that Arg1852 of the yeast cytoplasmic dynein could involve in the “glutamate switch” mechanism in cytoplasmic dynein 1 in lieu of the conserved Asn in AAA+ protein family.

scholarly journals Targeting Poison Exons to Treat Developmental and Epileptic Encephalopathy

2021 ◽  
pp. 1-6
Author(s):  
Miriam C. Aziz ◽  
Patricia N. Schneider ◽  
Gemma L. Carvill
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Autism Spectrum ◽  
Epileptic Encephalopathy ◽  
Nonsense Mediated Decay ◽  
Subsequent Degradation ◽  
Alternative Splicing Events ◽  
Genetic Epilepsies

Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic <i>SCN1A</i> variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.

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