title: Rescue of molybdenum cofactor biosynthesis in gephyrin-deficient mice by a Cnx1 transgene.
abstract: Gephyrin is a bifunctional protein which is essential for both synaptic clustering of inhibitory neurotransmitter receptors in the central nervous system and the biosynthesis of the molybdenum cofactor (MoCo) in peripheral tissues. Mice deficient in gephyrin die early postnatally and display a loss of glycine receptors (GlyRs) and many GABA(A) receptor (GABA(A)R) subtypes from postsynaptic sites. In addition, the activities of the MoCo-dependent enzymes xanthine dehydrogenase and sulfite oxidase are reduced to background levels in the liver and intestine of these animals. To genetically separate the different consequences of gephyrin deficiency, we expressed a transgene of the plant homolog Cnx1, known to rescue mammalian MoCo deficiency, on the background of gephyrin knockout mice. Cnx1 partially restored sulfite oxidase activity in the liver of the transgenic animals, whereas early lethality and the loss of GlyR clustering were unaltered. Our data suggest that the loss of neurotransmitter receptor clustering at inhibitory synapses causes the early lethality of gephyrin deficient mice.
authors.affiliation: Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, D-60528 Frankfurt/Main, Germany.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Grosskreutz
authors.forename: Heinrich
authors.initials: H
authors.lastname: Betz
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins / Q000235:genetics*; D001921:Brain / Q000502:physiology; D037281:Calnexin / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003067:Coenzymes; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017343:Genes, Plant; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008667:Metalloproteins / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D000090006:Molybdenum Cofactors; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000378:metabolism; D011621:Pteridines; D012333:RNA, Messenger / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D019076:Transgenes
chemical_list: D029681:Arabidopsis Proteins; D037281:Calnexin; D002352:Carrier Proteins; D003067:Coenzymes; D007770:L-Lactate Dehydrogenase; D008565:Membrane Proteins; D008667:Metalloproteins; D000090006:Molybdenum Cofactors; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011621:Pteridines; D012333:RNA, Messenger; D018091:Receptors, AMPA; D018009:Receptors, Glycine; C080351:CNX1 protein, Arabidopsis; C114561:GLRB protein, human; C491949:Glrb protein, mouse; C073441:gephyrin; C104724:glutamate receptor ionotropic, AMPA 4; C022261:molybdopterin