ATP9A

Last update 08 May 2025

Basic Info

Synonyms

ATP9A, ATPase class II type 9A, ATPase phospholipid transporting 9A (putative)

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Introduction

Plays a role in regulating membrane trafficking of cargo proteins, namely endosome to plasma membrane recycling, probably acting through RAB5 and RAB11 activation (PubMed:27733620, PubMed:30213940, PubMed:36604604). Also involved in endosome to trans-Golgi network retrograde transport (PubMed:27733620, PubMed:30213940). In complex with MON2 and DOP1B, regulates SNX3 retromer-mediated endosomal sorting of WLS, a transporter of Wnt morphogens in developing tissues. Participates in the formation of endosomal carriers that direct WLS trafficking back to Golgi, away from lysosomal degradation (PubMed:30213940). Appears to be implicated in intercellular communication by negatively regulating the release of exosomes (PubMed:30947313). The flippase activity towards membrane lipids and its role in membrane asymmetry remains to be proved (PubMed:30947313). Required for the maintenance of neurite morphology and synaptic transmission (By similarity).

100 Clinical Results associated with ATP9A

100 Translational Medicine associated with ATP9A

0 Patents (Medical) associated with ATP9A

Literatures (Medical) associated with ATP9A

01 Jul 2025·Life Science Alliance

Lipid flippases ATP9A and ATP9B form a complex and contribute to the exocytic pathway from the Golgi

Article

Author: Tanaka, Gaku ; Nakayama, Kazuhisa ; Muranaka, Yumeka ; Takatsu, Hiroyuki ; Katoh, Yohei ; Yagi, Tsukasa ; Shin, Hye-Won ; Nakabuchi, Riki

Type IV P-type ATPases (P4-ATPases) serve as lipid flippases, translocating membrane lipids from the exoplasmic (or luminal) leaflet to the cytoplasmic leaflet of lipid bilayers. In mammals, these P4-ATPases are localized to distinct subcellular compartments. ATP8A1 and ATP9A, members of the P4-ATPase family, are involved in endosome-mediated membrane trafficking, although the roles of P4-ATPases in the exocytic pathway remain to be clarified. ATP9A and ATP9B are located in the TGN, with ATP9A also present in endosomal compartments. This study revealed the overlapping roles of ATP9A and ATP9B in transporting VSVG from the Golgi to the plasma membrane within the exocytic pathway. Furthermore, we demonstrated that the flippase activities of ATP9A and ATP9B were crucial for the transport process. Notably, we discovered the formation of homomeric and/or heteromeric complexes between ATP9A and ATP9B. Therefore, ATP9A and ATP9B play a role in the exocytic pathway from the Golgi to the plasma membrane, forming either homomeric or heteromeric complexes.

01 Jan 2025·Human Mutation

Heterozygous Missense Variants in the ATPase Phospholipid Transporting 9A Gene, ATP9A, Alter Dendritic Spine Maturation and Cause Dominantly Inherited Nonsyndromic Intellectual Disability

Article

Author: Laumonnier, Frédéric ; Gasser, Brooklynn ; Bezieau, Stéphane ; Stamberger, Hannah ; Martínez-Delgado, Beatriz ; Abdallah, Hamza Hadj ; Hérenger, Yvan ; Vuillaume, Marie-Laure ; López-Martín, Estrella ; Barcia, Giulia ; Courtin, Thomas ; Barrero, María J ; Faivre, Laurence ; Cormier, Coline ; Küry, Sébastien ; Denommé-Pichon, Anne-Sophie ; Cordovado, Amélie ; Weckhuysen, Sarah ; Bermejo-Sánchez, Eva ; Vitobello, Antonio ; Toutain, Annick

Intellectual disability is a neurodevelopmental disorder, affecting 2%–3% of the population, with a genetic cause in the majority of cases. ATP9A (Online Mendelian Inheritance in Man (OMIM) ∗609126, NM_006045.3) has recently been added to the list of candidate genes involved in this disorder with the identification of biallelic truncating variants in patients with a neurodevelopmental disorder. In this study, we propose a novel mode of inheritance for ATP9A‐related disorders with the identification of five de novo heterozygous missense variants (p.(Thr393Arg), p.(Glu400Gln), p.(Lys461Glu), p.(Gly552Ala), and p.(His713Asp)), in patients with intellectual disability. In a patient with a similar phenotype, we also identified two truncating variants in ATP9A (p.(Arg145 ∗), p.(Glu901 ∗)), adding a novel family to the six already described in the literature with the recessive mode of inheritance. Functional studies were performed to assess the pathogenicity of these variants. Overexpression of four selected missense mutant forms of Atp9a in HeLa cells and in primary neuronal cultures led to a loss of mature dendritic spines. In HeLa cells, the endosomal localization of the protein encoded by three of these missense variants was preserved whereas the fourth remained blocked in the endoplasmic reticulum. To mimic the effect on neuronal morphology and spine density of nonsense variants, small hairpin RNAs (shRNAs) were used. They induced a decreased expression of ATP9A, affecting the neuronal arborization by decreasing the number of dendrites per neuron. Our results therefore demonstrate the pathogenicity of ATP9A heterozygous missense variants and confirm the role of ATP9A in neuronal maturation and in brain wiring during development. They strengthen the association of ATP9A with neurodevelopmental disorders and demonstrate that a double mode of inheritance should be considered for ATP9A‐related disorders.

01 Nov 2024·Current Biology

Dopey-dependent regulation of extracellular vesicles maintains neuronal morphology

Article

Author: Chisholm, Andrew D ; Colavita, Antonio ; Noblett, Nathaniel ; Wehman, Ann M ; Jin, Yishi ; Park, Seungmee ; Pitts, Lauren

Mature neurons maintain their distinctive morphology for extended periods in adult life. Compared to developmental neurite outgrowth, axon guidance, and target selection, relatively little is known of mechanisms that maintain the morphology of mature neurons. Loss of function in C. elegans dip-2, a member of the conserved lipid metabolic regulator Dip2 family, results in progressive overgrowth of neurites in adults. We find that dip-2 mutants display specific genetic interactions with sax-2, the C. elegans ortholog of Drosophila Furry and mammalian FRY. Combined loss of dip-2 and sax-2 results in failure to maintain neuronal morphology and elevated release of neuronal extracellular vesicles (EVs). By screening for suppressors of dip-2(0) sax-2(0) double mutant defects, we identified gain-of-function (gf) mutations in the conserved Dopey family protein PAD-1 and its associated phospholipid flippase TAT-5/ATP9A that restore normal neuronal morphology and normal levels of EV release to dip-2(0) sax-2(0) double mutants. Neuron-specific knockdown suggests that PAD-1(gf) can act cell autonomously in neurons. PAD-1(gf) displays increased association with the plasma membrane in oocytes and inhibits EV release in multiple cell types. Our findings uncover a novel functional network of DIP-2, SAX-2, PAD-1, and TAT-5 that maintains neuronal morphology and modulates EV release.

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ATP9A

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