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000295902 1001_ $$00000-0002-0391-1497$$aKopp, Johannes$$b0
000295902 245__ $$aGolgi pH elevation due to loss of V-ATPase subunit V0a2 function correlates with tissue-specific glycosylation changes and globozoospermia.
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000295902 520__ $$aLoss-of-function variants in ATP6V0A2, encoding the trans Golgi V-ATPase subunit V0a2, cause wrinkly skin syndrome (WSS), a connective tissue disorder with glycosylation defects and aberrant cortical neuron migration. We used knock-out (Atp6v0a2-/-) and knock-in (Atp6v0a2RQ/RQ) mice harboring the R755Q missense mutation selectively abolishing V0a2-mediated proton transport to investigate the WSS pathomechanism. Homozygous mutants from both strains displayed a reduction of growth, dermis thickness, and elastic fiber formation compatible with WSS. A hitherto unrecognized male infertility due to globozoospermia was evident in both mouse lines with impaired Golgi-derived acrosome formation and abolished mucin-type O-glycosylation in spermatids. Atp6v0a2-/- mutants showed enhanced fucosylation and glycosaminoglycan modification, but reduced levels of glycanated decorin and sialylation in skin and/or fibroblasts, which were absent or milder in Atp6v0a2RQ/RQ. Atp6v0a2RQ/RQ mutants displayed more abnormal migration of cortical neurons, correlating with seizures and a reduced O-mannosylation of α-dystroglycan. While anterograde transport within the secretory pathway was similarly delayed in both mutants the brefeldin A-induced retrograde fusion of Golgi membranes with the endoplasmic reticulum was less impaired in Atp6v0a2RQ/RQ. Measurement of the pH in the trans Golgi compartment revealed a shift from 5.80 in wildtype to 6.52 in Atp6v0a2-/- and 6.25 in Atp6v0a2RQ/RQ. Our findings suggest that altered O-glycosylation is more relevant for the WSS pathomechanism than N-glycosylation and leads to a secondary dystroglycanopathy. Most phenotypic and cellular properties correlate with the different degrees of trans Golgi pH elevation in both mutants underlining the fundamental relevance of pH regulation in the secretory pathway.
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000295902 650_7 $$2Other$$aCutis laxa
000295902 650_7 $$2Other$$aGlobozoospermia
000295902 650_7 $$2Other$$aGlycosylation
000295902 650_7 $$2Other$$aGolgi
000295902 650_7 $$2Other$$aNeuronal migration
000295902 650_7 $$2Other$$aSpermiogenesis
000295902 650_7 $$2Other$$aV-ATPase
000295902 650_7 $$2Other$$aVesicular trafficking
000295902 650_7 $$2Other$$apH-regulation
000295902 650_7 $$0EC 3.6.1.-$$2NLM Chemicals$$aVacuolar Proton-Translocating ATPases
000295902 650_2 $$2MeSH$$aAnimals
000295902 650_2 $$2MeSH$$aMale
000295902 650_2 $$2MeSH$$aGlycosylation
000295902 650_2 $$2MeSH$$aGolgi Apparatus: metabolism
000295902 650_2 $$2MeSH$$aMice
000295902 650_2 $$2MeSH$$aVacuolar Proton-Translocating ATPases: metabolism
000295902 650_2 $$2MeSH$$aVacuolar Proton-Translocating ATPases: genetics
000295902 650_2 $$2MeSH$$aHydrogen-Ion Concentration
000295902 650_2 $$2MeSH$$aMice, Knockout
000295902 650_2 $$2MeSH$$aTeratozoospermia: metabolism
000295902 650_2 $$2MeSH$$aTeratozoospermia: genetics
000295902 650_2 $$2MeSH$$aTeratozoospermia: pathology
000295902 650_2 $$2MeSH$$aMice, Inbred C57BL
000295902 650_2 $$2MeSH$$aHumans
000295902 650_2 $$2MeSH$$aFibroblasts: metabolism
000295902 7001_ $$00000-0001-8912-5851$$aJahn, Denise$$b1
000295902 7001_ $$00000-0002-7475-2972$$aVogt, Guido$$b2
000295902 7001_ $$00009-0009-9034-4440$$aPsoma, Anthi$$b3
000295902 7001_ $$0P:(DE-He78)319f5ff79bf5e1c826c5c2ae2c2c9a15$$aRatto, Edoardo$$b4$$udkfz
000295902 7001_ $$00009-0004-8330-4049$$aMorelle, Willy$$b5
000295902 7001_ $$00000-0001-9822-5694$$aStelzer, Nina$$b6
000295902 7001_ $$00000-0002-1095-4962$$aHausser, Ingrid$$b7
000295902 7001_ $$00009-0004-7638-5602$$aHoffmann, Anne$$b8
000295902 7001_ $$00000-0002-2126-7658$$ade Los Santos, Miguel Rodriguez$$b9
000295902 7001_ $$00000-0003-4943-198X$$aKoch, Leonard A$$b10
000295902 7001_ $$00000-0002-1075-7571$$aFischer-Zirnsak, Björn$$b11
000295902 7001_ $$00000-0001-6419-8747$$aThiel, Christian$$b12
000295902 7001_ $$0P:(DE-He78)c8525dbb77cddc5280375ea4a5e3c13e$$aPalm, Wilhelm$$b13$$udkfz
000295902 7001_ $$00000-0002-0170-868X$$aMeierhofer, David$$b14
000295902 7001_ $$00000-0003-2180-6735$$avan den Bogaart, Geert$$b15
000295902 7001_ $$00000-0001-5084-4015$$aFoulquier, François$$b16
000295902 7001_ $$00000-0003-3711-2746$$aMeinhardt, Andreas$$b17
000295902 7001_ $$00000-0002-4582-9838$$aKornak, Uwe$$b18
000295902 773__ $$0PERI:(DE-600)1458497-9$$a10.1007/s00018-024-05506-7$$gVol. 82, no. 1, p. 4$$n1$$p4$$tCellular and molecular life sciences$$v82$$x1420-682X$$y2025
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