De novo mutations of the ATP6V1A gene cause developmental encephalopathy with epilepsy

Fassio, Anna; Esposito, Alessandro; Kato, Mitsuhiro; Saitsu, Hirotomo; Mei, Davide; Marini, Carla; Conti, Valerio; Nakashima, Mitsuko; Okamoto, Nobuhiko; Turker, Akgun Olmez; Albuz, Burcu; Gündüz, Cavidan Nur Semerci; Yanagihara, Keiko; Belmonte, Elisa L.; Maragliano, Luca; Ramsey, Keri; Balak, Chris; Siniard, Ashley L.; Narayanan, Vinodh; Ohba, Chihiro; Shiina, Masaaki; Ogata, Kazuhiro; Matsumoto, Naomichi; Benfenati, Fabio; Guerrini, Renzo

doi:10.1093/brain/awy092

Cited by 70 publications

(56 citation statements)

References 60 publications

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“…Importantly, whereas ATP synthases are enriched in muscle for energy production, the V-ATPases are specifically enriched in brain for synaptic transmission (28). Mutations of V-ATPase are associated with neurological diseases (29).…”

Section: Metabolismmentioning

confidence: 99%

A Quantitative Proteome Map of the Human Body

Jiang

Wang

Lin

et al. 2019

Preprint

109

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Quantitative proteome study of 32 human tissues and integrated analysis with transcriptome data revealed that understanding protein levels could provide in-depth knowledge to post transcriptional or translational regulations, human metabolism, secretome, and diseases. AbstractDetermining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from 12,627 genes across 32 normal human tissue types prepared by the GTEx project. Known and new tissue specific or enriched proteins (5,499) were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode highly tissue specific proteins. Discordance in the sites of RNA expression and protein detection also revealed potential sites of synthesis and action of protein signaling molecules. Overall, these results provide an extraordinary resource, and demonstrate that understanding protein levels can provide insights into metabolism, regulation, secretome, and human diseases.

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Section: Metabolismmentioning

confidence: 99%

A Quantitative Proteome Map of the Human Body

Jiang

Wang

Lin

et al. 2019

Preprint

109

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“…v-ATPase is a component of the mTOR pathway and functions as a lysosome-associated machinery for amino acid sensing 49,50 . A 15 potential role of ATP6V1A in neuronal development was suggested by studying de novo mutations in this gene 51 . Yet, there are no prior studies linking changes in APT6V1A expression with LOAD pathogenesis.…”

Section: Bayesian Network Analysis Predicts Novel Key Drivers Of Synamentioning

confidence: 99%

“…ATP6V1A plays a unique role in synapse function 55 . Therefore, we determined whether ATP6V1A repression influenced spontaneous neuronal electric activity.…”

Section: Decreased Neuronal Activity In Atp6v1a-deficient Ngn2-neuronsmentioning

confidence: 99%

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Wang

Sekiya

et al. 2019

Preprint

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To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H + -ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

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“…Four cases with ATP6V1A mutations have been reported so far, all of them had preexisting developmental delay and fever-associated seizures, followed by epileptic encephalopathy. 1 Index child was developmentally normal, there were no episodes of fever-associated seizures. He presented with infantile spasms (IS) and neuroregression followed by refractory seizures.…”

Section: Discussionmentioning

confidence: 94%