Expanding the clinical and molecular spectrum of <scp><i>ATP6V1A</i></scp> related metabolic cutis laxa

Vogt, Guido; Choubassi, Naji El; Herczegfalvi, Ágnes; Kölbel, Heike; Lekaj, Anja; Schara, Ulrike; Holtgrewe, Manuel; Krause, Sabine; Horvath, Rita; Schuelke, Markus; Hübner, Christoph; Mundlos, Stefan; Roos, Andreas; Lochmüller, Hanns; Karcagi, Veronika; Kornak, Uwe; Fischer-Zirnsak, Björn

doi:10.1002/jimd.12341

Cited by 11 publications

(4 citation statements)

References 36 publications

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“…In particular, mutations in ATP6V1A, coding for the V 1 A member of the cytosolic V 1 complex, have been associated with epileptic encephalopathies and a broad spectrum of clinical severity. 14,16,[38][39][40] Altered ATP6V1A expression has been recently identified in Alzheimer's patient brains and proposed to represent a key factor for neuronal impairment and neurodegeneration. 20 In this scenario, clarifying the morphological and functional consequences of neuronal ATP6V1A loss is fundamental to unravel disease pathophysiology and design novel treatments.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, several mutations in genes coding for the various v‐ATPase subunits have been described in patients with neurodevelopmental disorders, often associated with epilepsy and intellectual disability. In particular, mutations in ATP6V1A , coding for the V 1 A member of the cytosolic V 1 complex, have been associated with epileptic encephalopathies and a broad spectrum of clinical severity 14,16,38–40 . Altered ATP6V1A expression has been recently identified in Alzheimer's patient brains and proposed to represent a key factor for neuronal impairment and neurodegeneration 20 .…”

Section: Discussionmentioning

confidence: 99%

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ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons

Esposito,

Pepe,

Cerullo

et al. 2024

Acta Physiologica

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AimUnderstanding the physiological role of ATP6V1A, a component of the cytosolic V1 domain of the proton pump vacuolar ATPase, in regulating neuronal development and function.MethodsModeling loss of function of Atp6v1a in primary murine hippocampal neurons and studying neuronal morphology and function by immunoimaging, electrophysiological recordings and electron microscopy.ResultsAtp6v1a depletion affects neurite elongation, stabilization, and function of excitatory synapses and prevents synaptic rearrangement upon induction of plasticity. These phenotypes are due to an overall decreased expression of the V1 subunits, that leads to impairment of lysosomal pH‐regulation and autophagy progression with accumulation of aberrant lysosomes at neuronal soma and of enlarged vacuoles at synaptic boutons.ConclusionsThese data suggest a physiological role of ATP6V1A in the surveillance of synaptic integrity and plasticity and highlight the pathophysiological significance of ATP6V1A loss in the alteration of synaptic function that is associated with neurodevelopmental and neurodegenerative diseases. The data further support the pivotal involvement of lysosomal function and autophagy flux in maintaining proper synaptic connectivity and adaptive neuronal properties.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons

Esposito,

Pepe,

Cerullo

et al. 2024

Acta Physiologica

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“…ATP6V1A encodes a component of vacuolar ATPase ( V-ATPase ). V-ATPase includes a cytosolic V1 domain and a transmembrane V0 domain, among which the V1 domain contains an ATP catalytic site [ 38 ]. ATP6V1A is involved in the suppression of acid secretion, growth retardation, trunk deformation, and homeostasis of calcium and sodium ion [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Cardiovascular Disease-Related Genes Based on the Co-Expression Network Analysis of Genome-Wide Blood Transcriptome

Lee

Hwang

Seo

et al. 2022

Cells

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Inference of co-expression network and identification of disease-related modules and gene sets can help us understand disease-related molecular pathophysiology. We aimed to identify a cardiovascular disease (CVD)-related transcriptomic signature, specifically, in peripheral blood tissue, based on differential expression (DE) and differential co-expression (DcoE) analyses. Publicly available blood sample datasets for coronary artery disease (CAD) and acute coronary syndrome (ACS) statuses were integrated to establish a co-expression network. A weighted gene co-expression network analysis was used to construct modules that include genes with highly correlated expression values. The DE criterion is a linear regression with module eigengenes for module-specific genes calculated from principal component analysis and disease status as the dependent and independent variables, respectively. The DcoE criterion is a paired t-test for intramodular connectivity between disease and matched control statuses. A total of 21 and 23 modules were established from CAD status- and ACS-related datasets, respectively, of which six modules per disease status (i.e., obstructive CAD and ACS) were selected based on the DE and DcoE criteria. For each module, gene–gene interactions with extremely high correlation coefficients were individually selected under the two conditions. Genes displaying a significant change in the number of edges (gene–gene interaction) were selected. A total of 6, 10, and 7 genes in each of the three modules were identified as potential CAD status-related genes, and 14 and 8 genes in each of the two modules were selected as ACS-related genes. Our study identified gene sets and genes that were dysregulated in CVD blood samples. These findings may contribute to the understanding of CVD pathophysiology.

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“…An imbalance in this process leads to acidification. So far, 4 patients have been reported, of which two exhibited SD (with tortuous aortic arch), LQTS with incomplete RBBB, HCM and progressive cardiac failure [14,405,406] (Table 5, Supplementary Tables S2 and S3). Likewise, mutations affecting the ATP6V1E1 gene on chromosome 22q11.21 encoding another subunit of this complex are the cause of an AR inherited CDG, known as cutis laxa type IIC [OMIM:617402].…”

Section: V-atpase Complex Defects Atp6v1a-cdg and Atp6v1e1-cdgmentioning

confidence: 99%

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Conte,

Sam,

Lefeber

et al. 2023

IJMS

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Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

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Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa

Cited by 11 publications

References 36 publications

ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons

ATP6V1A is required for synaptic rearrangements and plasticity in murine hippocampal neurons

Identification of Cardiovascular Disease-Related Genes Based on the Co-Expression Network Analysis of Genome-Wide Blood Transcriptome

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

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