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@ARTICLE{Kopp:295902,
      author       = {J. Kopp and D. Jahn and G. Vogt and A. Psoma and E.
                      Ratto$^*$ and W. Morelle and N. Stelzer and I. Hausser and
                      A. Hoffmann and M. R. de Los Santos and L. A. Koch and B.
                      Fischer-Zirnsak and C. Thiel and W. Palm$^*$ and D.
                      Meierhofer and G. van den Bogaart and F. Foulquier and A.
                      Meinhardt and U. Kornak},
      title        = {{G}olgi p{H} elevation due to loss of {V}-{ATP}ase subunit
                      {V}0a2 function correlates with tissue-specific
                      glycosylation changes and globozoospermia.},
      journal      = {Cellular and molecular life sciences},
      volume       = {82},
      number       = {1},
      issn         = {1420-682X},
      address      = {Cham (ZG)},
      publisher    = {Springer International Publishing AG},
      reportid     = {DKFZ-2024-02716},
      pages        = {4},
      year         = {2025},
      abstract     = {Loss-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.},
      keywords     = {Animals / Male / Glycosylation / Golgi Apparatus:
                      metabolism / Mice / Vacuolar Proton-Translocating ATPases:
                      metabolism / Vacuolar Proton-Translocating ATPases: genetics
                      / Hydrogen-Ion Concentration / Mice, Knockout /
                      Teratozoospermia: metabolism / Teratozoospermia: genetics /
                      Teratozoospermia: pathology / Mice, Inbred C57BL / Humans /
                      Fibroblasts: metabolism / Cutis laxa (Other) /
                      Globozoospermia (Other) / Glycosylation (Other) / Golgi
                      (Other) / Neuronal migration (Other) / Spermiogenesis
                      (Other) / V-ATPase (Other) / Vesicular trafficking (Other) /
                      pH-regulation (Other) / Vacuolar Proton-Translocating
                      ATPases (NLM Chemicals)},
      cin          = {A330},
      ddc          = {610},
      cid          = {I:(DE-He78)A330-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39680136},
      doi          = {10.1007/s00018-024-05506-7},
      url          = {https://inrepo02.dkfz.de/record/295902},
}