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Gene Review

GPHN  -  gephyrin

Homo sapiens

Synonyms: GEPH, GPH, GPHRYN, Gephyrin, HKPX1, ...
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Disease relevance of GPHN


High impact information on GPHN

  • The beta-subunit is responsible for anchoring GlyRs to the subsynaptic cytoskeleton via the cytoplasmic protein gephyrin [5].
  • For example, glycine receptors are associated with gephyrin, a protein that mediates linkage to synaptic microtubules, thus raising obvious analogies to muscle AChR and the 43K protein [6].
  • The interaction with gephyrin ascribes a function to the large amino-terminal region of an ATM-related protein and reveals a role in signal transduction for the clustering protein gephyrin [7].
  • In mammalian cells RAFT1 interacted with gephyrin, a widely expressed protein necessary for the clustering of glycine receptors at the cell membrane of neurons [7].
  • Membrane apposition of the tubulin-binding protein gephyrin is essential for the recruitment of inhibitory glycine receptors and GABAA receptors to developing postsynaptic sites [8].

Chemical compound and disease context of GPHN


Biological context of GPHN


Anatomical context of GPHN


Associations of GPHN with chemical compounds

  • Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia [10].
  • Mice deficient in gephyrin develop a hereditary molybdenum cofactor deficiency and a neurological phenotype that mimics startle disease (hyperekplexia) [10].
  • Highlighting its central role in this receptor anchoring scaffold, gephyrin interacts with a number of proteins, including the neurospecific guanine nucleotide exchange factor collybistin [15].
  • The Crystal Structure of Cdc42 in Complex with Collybistin II, a Gephyrin-interacting Guanine Nucleotide Exchange Factor [15].
  • Recent studies have demonstrated that gephyrin, a protein first identified as a component of the glycine receptor (GlyR) complex, is colocalized with several subtypes of GABAA receptors and is involved in the stabilization of postsynaptic GABAA receptor clusters [16].

Physical interactions of GPHN


Co-localisations of GPHN

  • In the in vivo retina, more than 80% of the gephyrin clusters colocalized with extracellular agrin [18].

Regulatory relationships of GPHN

  • Our data suggest that collybistin II regulates the membrane deposition of gephyrin by activating a GTPase of the Rho/Rac family [19].

Other interactions of GPHN


Analytical, diagnostic and therapeutic context of GPHN


  1. t(11;14)(q23;q24) generates an MLL-human gephyrin fusion gene along with a de facto truncated MLL in acute monoblastic leukemia. Kuwada, N., Kimura, F., Matsumura, T., Yamashita, T., Nakamura, Y., Wakimoto, N., Ikeda, T., Sato, K., Motoyoshi, K. Cancer Res. (2001) [Pubmed]
  2. The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells. David-Watine, B. Gene (2001) [Pubmed]
  3. Autoimmunity to gephyrin in Stiff-Man syndrome. Butler, M.H., Hayashi, A., Ohkoshi, N., Villmann, C., Becker, C.M., Feng, G., De Camilli, P., Solimena, M. Neuron (2000) [Pubmed]
  4. Crystal structure of the gephyrin-related molybdenum cofactor biosynthesis protein MogA from Escherichia coli. Liu, M.T., Wuebbens, M.M., Rajagopalan, K.V., Schindelin, H. J. Biol. Chem. (2000) [Pubmed]
  5. Molecular structure and function of the glycine receptor chloride channel. Lynch, J.W. Physiol. Rev. (2004) [Pubmed]
  6. Regulation of ion channel distribution at synapses. Froehner, S.C. Annu. Rev. Neurosci. (1993) [Pubmed]
  7. Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling. Sabatini, D.M., Barrow, R.K., Blackshaw, S., Burnett, P.E., Lai, M.M., Field, M.E., Bahr, B.A., Kirsch, J., Betz, H., Snyder, S.H. Science (1999) [Pubmed]
  8. Clustering of inhibitory neurotransmitter receptors at developing postsynaptic sites: the membrane activation model. Kneussel, M., Betz, H. Trends Neurosci. (2000) [Pubmed]
  9. Distribution of glycine receptor subunits on primate retinal ganglion cells: a quantitative analysis. Lin, B., Martin, P.R., Solomon, S.G., Grünert, U. Eur. J. Neurosci. (2000) [Pubmed]
  10. Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia. Rees, M.I., Harvey, K., Ward, H., White, J.H., Evans, L., Duguid, I.C., Hsu, C.C., Coleman, S.L., Miller, J., Baer, K., Waldvogel, H.J., Gibbon, F., Smart, T.G., Owen, M.J., Harvey, R.J., Snell, R.G. J. Biol. Chem. (2003) [Pubmed]
  11. GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24). Eguchi, M., Eguchi-Ishimae, M., Seto, M., Morishita, K., Suzuki, K., Ueda, R., Ueda, K., Kamada, N., Greaves, M. Genes Chromosomes Cancer (2001) [Pubmed]
  12. The small oligomerization domain of gephyrin converts MLL to an oncogene. Eguchi, M., Eguchi-Ishimae, M., Greaves, M. Blood (2004) [Pubmed]
  13. The state of the actin cytoskeleton determines its association with gephyrin: role of ena/VASP family members. Bausen, M., Fuhrmann, J.C., Betz, H., O'sullivan, G.A. Mol. Cell. Neurosci. (2006) [Pubmed]
  14. Distribution of gephyrin in the human brain: an immunohistochemical analysis. Waldvogel, H.J., Baer, K., Snell, R.G., During, M.J., Faull, R.L., Rees, M.I. Neuroscience (2003) [Pubmed]
  15. The Crystal Structure of Cdc42 in Complex with Collybistin II, a Gephyrin-interacting Guanine Nucleotide Exchange Factor. Xiang, S., Kim, E.Y., Connelly, J.J., Nassar, N., Kirsch, J., Winking, J., Schwarz, G., Schindelin, H. J. Mol. Biol. (2006) [Pubmed]
  16. Mini-review: gephyrin, a major postsynaptic protein of GABAergic synapses. Sassoè-Pognetto, M., Fritschy, J.M. Eur. J. Neurosci. (2000) [Pubmed]
  17. Identification of a gephyrin-binding motif in the GDP/GTP exchange factor collybistin. Grosskreutz, Y., Hermann, A., Kins, S., Fuhrmann, J.C., Betz, H., Kneussel, M. Biol. Chem. (2001) [Pubmed]
  18. Agrin is synthesized by retinal cells and colocalizes with gephyrin [corrected]. Mann, S., Kröger, S. Mol. Cell. Neurosci. (1996) [Pubmed]
  19. Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Kins, S., Betz, H., Kirsch, J. Nat. Neurosci. (2000) [Pubmed]
  20. Interactions of drebrin and gephyrin with profilin. Mammoto, A., Sasaki, T., Asakura, T., Hotta, I., Imamura, H., Takahashi, K., Matsuura, Y., Shirao, T., Takai, Y. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  21. Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Reiss, J., Johnson, J.L. Hum. Mutat. (2003) [Pubmed]
  22. Hydrophobic interactions mediate binding of the glycine receptor beta-subunit to gephyrin. Kneussel, M., Hermann, A., Kirsch, J., Betz, H. J. Neurochem. (1999) [Pubmed]
  23. Association of gephyrin and glycine receptors in the human brainstem and spinal cord: an immunohistochemical analysis. Baer, K., Waldvogel, H.J., During, M.J., Snell, R.G., Faull, R.L., Rees, M.I. Neuroscience (2003) [Pubmed]
  24. Chorein deficiency leads to upregulation of gephyrin and GABA(A) receptor. Kurano, Y., Nakamura, M., Ichiba, M., Matsuda, M., Mizuno, E., Kato, M., Izumo, S., Sano, A. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  25. Mass Spectrometric Analysis of Glycine Receptor-associated Gephyrin Splice Variants. Paarmann, I., Schmitt, B., Meyer, B., Karas, M., Betz, H. J. Biol. Chem. (2006) [Pubmed]
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