Disease relevance of GPHN

• We analyzed one patient with de novo acute monoblastic leukemia with t(11;14)(q23;q24) and identified that a human homologue of gephyrin (human gephyrin) fused with MLL [1].
• The precise localization of the gephyrin gene allowed us to exclude it from being a candidate for the autosomal dominant spastic paraplegia, the locus of which maps to 14q between markers D14S259 and D14S1018 [2].
• We report here the identification of high-titer autoantibodies directed against gephyrin in a patient with clinical features of SMS and mediastinal cancer [3].
• Autoimmunity to gephyrin in Stiff-Man syndrome [3].
• Crystal structure of the gephyrin-related molybdenum cofactor biosynthesis protein MogA from Escherichia coli [4].

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

• Immunoreactive (IR) puncta representing glycine receptor or gephyrin clusters were found on the proximal and the distal dendrites of all ganglion cell types investigated [9].

Biological context of GPHN

• Mutation analysis of GPHN exons in hyperekplexia patients revealed a missense mutation (A28T) in one patient causing an amino acid substitution (N10Y) [10].
• This suggests that MLL-GPHN may have been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks, followed by error-prone DNA repair via non-homologous end joining [11].
• Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24 [11].
• The human gephyrin (GPHN) gene: structure, chromosome localization and expression in non-neuronal cells [2].
• The small oligomerization domain of gephyrin converts MLL to an oncogene [12].

Anatomical context of GPHN

• Therefore, the N10Y mutation and alternative splicing of GPHN transcripts do not affect interactions with GlyRs but may affect other interactions with the cytoskeleton or gephyrin accessory proteins [10].
• Gephyrin is a rat glycine receptor-associated protein, which forms submembranous complexes and anchor glycine or gamma-aminobutyric acidA receptors to microtubules [1].
• While gephyrin was not associated with microfilaments in transfected cells, it colocalized with G-actin and cytochalasin-D-induced F-actin patches [13].
• The spinal cord also showed high levels of gephyrin immunoreactivity [14].
• Gephyrin immunoreactivity was also observed on neurons in the thalamus, globus pallidus and substantia nigra [14].

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

• Our data suggest that Mena binding to F-actin allows for gephyrin recruitment to the leading edge of uncapped actin filaments [13].
• Furthermore, in vitro gephyrin bound simultaneously to both collybistin and the GlyR beta-subunit binding motif [17].

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

• Interactions of drebrin and gephyrin with profilin [20].
• Disease-causing mutations have been identified in three of these genes: MOCS1, MOCS2, and GEPH [21].
• Here we describe two splice variants of a novel gephyrin-binding protein, termed collybistin I and II, which belong to the family of dbl-like GDP/GTP exchange factors (GEFs) [19].
• The state of the actin cytoskeleton determines its association with gephyrin: role of ena/VASP family members [13].
• In the hippocampus, intense staining was observed on the granule cells of the dentate gyrus, and neurons of the CA1 and CA3 regions showed intense punctate gephyrin staining on their apical dendrites and cell bodies [14].

Analytical, diagnostic and therapeutic context of GPHN

• Gephyrin cDNAs were isolated, and subsequent RT-PCR analysis from human tissues demonstrated the presence of five alternatively spliced GPHN exons concentrated in the central linker region of the gene [10].
• Here, we localized amino acid residues implicated in gephyrin binding by site-directed mutagenesis [22].
• We have studied the distribution of gephyrin and glycine receptor subunits in the human brainstem and spinal cord using immunohistochemistry at light and confocal laser scanning microscopy levels [23].
• In this study, a comparative microarray analysis of gene expression in the striatum revealed an increased level of gephyrin gene expression in the ChAc-model mice compared with wild type mice [24].
• Gephyrin variants were purified from rat spinal cord, brain, and liver by binding to the glutathione S-transferase-tagged GlyRbeta loop or copurified with native GlyR from spinal cord by affinity chromatography and analyzed by mass spectrometry [25].

References