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FLASH GENE

Symbol

GPHN

contributors: mct/npt/pgu - updated : 09-11-2016

HGNC name	gephyrin
HGNC id	15465

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	EEOC2 epileptic encephalopathy, childhood onset 2 MOCODC molybdenum cofactor deficiency, type C STHE2 Startle disease, hyperekplexia 2
Location	14q23.3      Physical location : 66.974.124 - 67.648.523
Synonym symbol(s)	GEPH, GPH, GPHRYN, KIAA1385, HKPX1
EC.number	2.10.1.1/2.7.7.75

DNA

TYPE	functioning gene
STRUCTURE	674.40 kb     23 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001024218 22 - 4219 NP_001019389 79.6 736 - 2001 11418245 Geph2 NM_020806 23 - 4318 NP_065857 83.3 769 - 2001 11418245 GephP1

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon   highly   liver         Endocrine thyroid       highly Hearing/Equilibrium ear       highly Nervous brain         Reproductive male system prostate       Respiratory respiratory tract larynx     highly Urinary kidney

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N terminal homologous to the bacterial protein MogA, with conserved N-terminal G- and C-terminal E-domain, connected by the central (C-) domain (
	a small 15-AAs tubulin-binding domain necessary and sufficient for fusion with MLL in leukemia
	C terminal domain homolog to the bacterial MoeA believed to activate molybedenum before its incorporation into molybdopterin

HOMOLOGY

interspecies

homolog to Drosophila Cinnamon

Homologene

FAMILY	in the N-terminal section : moaB/mog family
	in the C-terminal section : moeA family

CATEGORY

enzyme , structural protein , receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytoskeleton
text	mainly expressed in the membrane and cytoplasm of neurons in temporal lobe epileptic foci
	its presence in a cytosolic 600 kDa protein complex suggests that its metabolic and/or other non-neuronal functions are exerted in the cytoplasm and are not confined to a particular subcellular compartment

basic FUNCTION	neurotransmitter receptor clustering and anchoring protein to subsynaptic microtubules of inhibitory ion channel receptors
	third step of molybenum cofactor biosynthesis in non neuronal tissues (insertion of molybdenum into molybdobiopterin)
	microtubule-associated protein involved in membrane protein-cytoskeleton interactions
	responsible for molybdenum cofactor synthesis and the clustering of glycine and GABA(A) receptors at inhibitory synapses
	postsynaptic scaffolding protein participated in clustering GABA(A) receptors at inhibitory synapses
	major protein determinant for the clustering of inhibitory neurotransmitter receptors
	major postsynaptic scaffolding protein at inhibitory synapses
	multimeric scaffolding protein gephyrin forms post-synaptic clusters at inhibitory sites, thereby anchoring inhibitory glycine (GLYR) and subsets of &
	947;-aminobutyric acid type A (GABAA) receptors
	is a scaffold protein essential for the postsynaptic clustering of inhibitory glycine and different subtypes of GABA(A) receptors
	postsynaptic scaffolding protein, essential for the clustering of glycine and gamma-aminobutyric acid type-A receptors (GABAARs) at inhibitory synapse
	vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis and other diverse functions
	is a central player at inhibitory postsynapses, directly binds and organizes GABAA and glycine receptors (GABAARs and GlyRs), and is thereby indispensable for normal inhibitory neurotransmission

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

nervous system

PATHWAY

metabolism

signaling

neurotransmission

a component	component of the glycine receptor
	collybistin-gephyrin (ARHGEF9/GPHN)complex has an intimate role in the clustering of GABA(A)Rs containing the alpha2 subunit

INTERACTION

DNA

RNA

small molecule

protein	glycine receptor beta subunit, GABAA receptors tubulin
	interacts with GABARAP
	formation of gephyrin scaffolds at inhibitory synapses requires an intact ARHGEF9 PH-domain but is CDC42-independent
	VPS35 binding to gephyrin
	interacting with GABRA1, GABRA3
	GPHN-binding protein AHRGEF9 is involved in regulating the phosphorylation of GPHN
	ARHGEF9 and CDK5 are involved in regulating the phosphorylation of GPHN at postsynaptic membrane specializations
	CDK5 plays likely an essential role for the stability of GPHN-dependent GABAA receptor clusters in hippocampal neurons
	NLGN2 is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein GPHN in the post-synaptic density
	PIN1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NLGN2/GPHN interaction
	intimate association of GABRA5 with GPHN, resulting in constant synaptic levels of GABRA5 throughout circuit formation that regulates neuronal development
	GSK3B regulates the sorting of GPHN and NLGN2 complexes in a KIF5A-dependent manner
	PKC-dependent phosphorylation of GAP43 plays a critical role in regulating postsynaptic GPHN aggregation in developing GABAergic synapses
	neuron-specific ARHGEF9 interacts with EIF3A, and its binding partner GPHN associates with MTOR
	EPHA7 regulates GPHN clustering and the maintenance of inhibitory synaptic connectivity via MTOR signalling

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

MOCODC , STHE2 , EEOC2

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral fusion       with MLL in t(11;14) (q23;q24) in acute monoblastic leukemia constitutional     --low   significantly lower in the temporal neocortex of temporal lobe epilepsy patients compared to the controls constitutional     --low   in Alzheimer Disease

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	Gephyrin-deficient (geph(-/-)) mice die after birth due to disinhibition of motor and sensory pathways resulting from a lack of postsynaptic glycine receptor and GABA(A) receptor clusters