AGRN (agrin)

Gene

• Entrez ID: 375790
• Gene name: Agrin
• Gene symbol: AGRN
• Synonyms: AGRIN, CMS8, CMSPPD
• Chromosome: 1
• Chromosome location: 1p36.33
• Summary: This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs113020870	C>T	Likely-benign, conflicting-interpretations-of-pathogenicity	Non coding transcript variant, synonymous variant, coding sequence variant
rs116836855	C>T	Conflicting-interpretations-of-pathogenicity, uncertain-significance	Non coding transcript variant, missense variant, coding sequence variant
rs141603403	C>G,T	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant, non coding transcript variant
rs143324306	G>A	Conflicting-interpretations-of-pathogenicity, benign-likely-benign	Coding sequence variant, non coding transcript variant, missense variant
rs145444272	G>A	Conflicting-interpretations-of-pathogenicity, benign-likely-benign	Coding sequence variant, non coding transcript variant, missense variant
rs146243145	G>A	Conflicting-interpretations-of-pathogenicity	Missense variant, coding sequence variant, non coding transcript variant
rs199476396	G>C	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant
rs201073369	G>A,C	Benign, conflicting-interpretations-of-pathogenicity, likely-benign	Genic upstream transcript variant, missense variant, coding sequence variant, non coding transcript variant
rs536657086	C>T	Likely-benign, conflicting-interpretations-of-pathogenicity	Synonymous variant, non coding transcript variant, coding sequence variant
rs544749044	C>T	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant, non coding transcript variant
rs587777298	G>T	Pathogenic	Coding sequence variant, missense variant, non coding transcript variant
rs587777299	C>T	Pathogenic	Stop gained, coding sequence variant, non coding transcript variant
rs750176911	C>G,T	Likely-pathogenic	Coding sequence variant, non coding transcript variant, stop gained, missense variant
rs756623659	G>A	Pathogenic	Genic upstream transcript variant, missense variant, coding sequence variant, non coding transcript variant
rs763818876	G>A	Pathogenic	Non coding transcript variant, coding sequence variant, missense variant
rs764160563	G>A	Pathogenic	Non coding transcript variant, coding sequence variant, missense variant
rs779170859	T>C	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, missense variant, non coding transcript variant
rs879253787	A>G,T	Pathogenic	Missense variant, coding sequence variant, non coding transcript variant, genic upstream transcript variant
rs879253788	->C	Pathogenic	Coding sequence variant, frameshift variant, non coding transcript variant
rs1239736447	C>G,T	Pathogenic	Synonymous variant, non coding transcript variant, coding sequence variant, stop gained
rs1553178276	->T	Likely-pathogenic	Non coding transcript variant, frameshift variant, coding sequence variant
rs1557700705	GCCAGGAGAATGTCTTCAAGAAGTTCGACGGCCC>-	Pathogenic	Coding sequence variant, frameshift variant, non coding transcript variant
rs1557721600	T>C	Likely-pathogenic	Coding sequence variant, missense variant, non coding transcript variant
rs1570190059	->CGGGC	Likely-pathogenic	Frameshift variant, non coding transcript variant, coding sequence variant
rs1570193864	GCGCCTGCGCC>-	Pathogenic	Frameshift variant, non coding transcript variant, coding sequence variant
rs1570195582	->CCCG	Pathogenic	Frameshift variant, non coding transcript variant, coding sequence variant
rs1570242061	CGACGCCTCCTGGGACCTCGGTCCCGGTCCCGTCTTCCTCCATCCAGGACCAACCT>-	Likely-pathogenic	Intron variant, non coding transcript variant, splice acceptor variant, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT001391	hsa-miR-1-3p	pSILAC, Proteomics;Other	18668040
MIRT020958	hsa-miR-155-5p	Proteomics	17881434
MIRT031889	hsa-miR-16-5p	Proteomics	18668040
MIRT499101	hsa-miR-4758-3p	PAR-CLIP	24398324
MIRT499102	hsa-miR-4632-3p	PAR-CLIP	24398324
MIRT499103	hsa-miR-500b-3p	PAR-CLIP	24398324
MIRT499104	hsa-miR-4323	PAR-CLIP	24398324

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001523	Process	Retinoid metabolic process	TAS
GO:0002162	Function	Dystroglycan binding	ISS
GO:0005200	Function	Structural constituent of cytoskeleton	TAS	9652404
GO:0005201	Function	Extracellular matrix structural constituent	RCA	20551380, 27068509, 27559042, 28675934
GO:0005509	Function	Calcium ion binding	ISS
GO:0005515	Function	Protein binding	IPI	9417121, 21078624
GO:0005576	Component	Extracellular region	TAS
GO:0005604	Component	Basement membrane	IDA	9405491
GO:0005796	Component	Golgi lumen	TAS
GO:0005886	Component	Plasma membrane	TAS
GO:0006024	Process	Glycosaminoglycan biosynthetic process	TAS
GO:0006027	Process	Glycosaminoglycan catabolic process	TAS
GO:0007010	Process	Cytoskeleton organization	IEA
GO:0007165	Process	Signal transduction	TAS	9652404
GO:0007213	Process	G protein-coupled acetylcholine receptor signaling pathway	TAS	9405491
GO:0007528	Process	Neuromuscular junction development	IBA	21873635
GO:0009887	Process	Animal organ morphogenesis	IBA	21873635
GO:0009888	Process	Tissue development	IBA	21873635
GO:0016021	Component	Integral component of membrane	IEA
GO:0030198	Process	Extracellular matrix organization	TAS
GO:0033691	Function	Sialic acid binding	ISS
GO:0035374	Function	Chondroitin sulfate binding	ISS
GO:0043113	Process	Receptor clustering	IBA	21873635
GO:0043113	Process	Receptor clustering	IDA	15340048
GO:0043113	Process	Receptor clustering	IMP	9151673
GO:0043202	Component	Lysosomal lumen	TAS
GO:0043236	Function	Laminin binding	TAS	9652404
GO:0043395	Function	Heparan sulfate proteoglycan binding	ISS
GO:0043547	Process	Positive regulation of GTPase activity	ISS
GO:0045162	Process	Clustering of voltage-gated sodium channels	TAS	9405491
GO:0045202	Component	Synapse	ISS
GO:0045887	Process	Positive regulation of synaptic growth at neuromuscular junction	ISS
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	ISS
GO:0050808	Process	Synapse organization	TAS	9652404
GO:0051491	Process	Positive regulation of filopodium assembly	ISS
GO:0062023	Component	Collagen-containing extracellular matrix	HDA	23658023, 27068509, 27559042, 28675934
GO:0062023	Component	Collagen-containing extracellular matrix	HDA	20551380
GO:0062023	Component	Collagen-containing extracellular matrix	IDA	17628813
GO:0062023	Component	Collagen-containing extracellular matrix	TAS	22261194
GO:0070062	Component	Extracellular exosome	HDA	19199708, 20458337, 23533145

Other IDs

• MIM: 103320
• HGNC: 329
• e!Ensembl: ENSG00000188157

Protein

• UniProt ID: O00468
• Protein name: Agrin [Cleaved into: Agrin N-terminal 110 kDa subunit; Agrin C-terminal 110 kDa subunit; Agrin C-terminal 90 kDa fragment (C90); Agrin C-terminal 22 kDa fragment (C22)]
• Protein function: [Isoform 1]: heparan sulfate basal lamina glycoprotein that plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ) and directs key events in postsynaptic differentiation. Component of the AGRN-LRP4 receptor complex that induces the phosphorylation and activation of MUSK. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Calcium ions are required for maximal AChR clustering. AGRN function in neurons is highly regulated by alternative splicing, glycan binding and proteolytic processing. Modulates calcium ion homeostasis in neurons, specifically by inducing an increase in cytoplasmic calcium ions. Functions differentially in the central nervous system (CNS) by inhibiting the alpha(3)-subtype of Na+/K+-ATPase and evoking depolarization at CNS synapses. This secreted isoform forms a bridge, after release from motor neurons, to basal lamina through binding laminin via the NtA domain.; [Isoform 2]: transmembrane form that is the predominate form in neurons of the brain, induces dendritic filopodia and synapse formation in mature hippocampal neurons in large part due to the attached glycosaminoglycan chains and the action of Rho-family GTPases.; Isoform 1, isoform 4 and isoform 5: neuron-specific (z+) isoforms that contain C-terminal insertions of 8-19 AA are potent activators of AChR clustering. Isoform 5, agrin (z+8), containing the 8-AA insert, forms a receptor complex in myotubules containing the neuronal AGRN, the muscle-specific kinase MUSK and LRP4, a member of the LDL receptor family. The splicing factors, NOVA1 and NOVA2, regulate AGRN splicing and production of the 'z' isoforms.; Isoform 3 and isoform 6: lack any 'z' insert, are muscle-specific and may be involved in endothelial cell differentiation.; [Agrin N-terminal 110 kDa subunit]: is involved in regulation of neurite outgrowth probably due to the presence of the glycosaminoglcan (GAG) side chains of heparan and chondroitin sulfate attached to the Ser/Thr- and Gly/Ser-rich regions. Also involved in modulation of growth factor signaling (By similarity). ; [Agrin C-terminal 22 kDa fragment]: this released fragment is important for agrin signaling and to exert a maximal dendritic filopodia-inducing effect. All 'z' splice variants (z+) of this fragment also show an increase in the number of filopodia.
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF03146	NtA	31 → 146	Agrin NtA domain	Domain
  PF07648	Kazal_2	197 → 242	Kazal-type serine protease inhibitor domain	Domain
  PF07648	Kazal_2	270 → 317	Kazal-type serine protease inhibitor domain	Domain
  PF00050	Kazal_1	335 → 389	Kazal-type serine protease inhibitor domain	Domain
  PF07648	Kazal_2	411 → 461	Kazal-type serine protease inhibitor domain	Domain
  PF07648	Kazal_2	489 → 534	Kazal-type serine protease inhibitor domain	Domain
  PF07648	Kazal_2	552 → 599	Kazal-type serine protease inhibitor domain	Domain
  PF07648	Kazal_2	616 → 669	Kazal-type serine protease inhibitor domain	Domain
  PF07648	Kazal_2	704 → 750	Kazal-type serine protease inhibitor domain	Domain
  PF00053	Laminin_EGF	793 → 844	Laminin EGF domain	Domain
  PF00053	Laminin_EGF	847 → 901	Laminin EGF domain	Domain
  PF07648	Kazal_2	923 → 969	Kazal-type serine protease inhibitor domain	Domain
  PF01390	SEA	1132 → 1237	SEA domain	Family
  PF00008	EGF	1333 → 1365	EGF-like domain	Domain
  PF00054	Laminin_G_1	1400 → 1531	Laminin G domain	Domain
  PF00008	EGF	1553 → 1584	EGF-like domain	Domain
  PF00054	Laminin_G_1	1668 → 1803	Laminin G domain	Domain
  PF00054	Laminin_G_1	1920 → 2051	Laminin G domain	Domain

• Sequence:

  MAGRSHPGPLRPLLPLLVVAACVLPGAGGTCPERALERREEEANVVLTGTVEEILNVDPV
  QHTYSCKVRVWRYLKGKDLVARESLLDGGNKVVISGFGDPLICDNQVSTGDTRIFFVNPA
  PPYLWPAHKNELMLNSSLMRITLRNLEEVEFCVEDKPGTHFTPVPPTPPDACRGMLCGFG
  AVCEPNAEGPGRASCVCKKSPCPSVVAPVCGSDASTYSNECELQRAQCSQQRRIRLLSRG
  PCGSRDPCSNVTCSFGSTCARSADGLTASCLCPATCRGAPEGTVCGSDGADYPGECQLLR
  RACARQENVFKKFDGPCDPCQGALPDPSRSCRVNPRTRRPEMLLRPESCPARQAPVCGDD
  GVTYENDCVMGRSGAARGLLLQKVRSGQCQGRDQCPEPCRFNAVCLSRRGRPRCSCDRVT
  CDGAYRPVCAQDGRTYDSDCWRQQAECRQQRAIPSKHQGPCDQAPSPCLGVQCAFGATCA
  VKNGQAACECLQACSSLYDPVCGSDGVTYGSACELEATACTLGREIQVARKGPCDRCGQC
  RFGALCEAETGRCVCPSECVALAQPVCGSDGHTYPSECMLHVHACTHQISLHVASAGPCE
  TCGDAVCAFGAVCSAGQCVCPRCEHPPPGPVCGSDGVTYGSACELREAACLQQTQIEEAR
  AGPCEQAECGSGGSGSGEDGDCEQELCRQRGGIWDEDSEDGPCVCDFSCQSVPGSPVCGS
  DGVTYSTECELKKARCESQRGLYVAAQGACRGPTFAPLPPVAPLHCAQTPYGCCQDNITA
  ARGVGLAGCPSACQCNPHGSYGGTCDPATGQCSCRPGVGGLRCDRCEPGFWNFRGIVTDG
  RSGCTPCSCDPQGAVRDDCEQMTGLCSCKPGVAGPKCGQCPDGRALGPAGCEADASAPAT
  CAEMRCEFGARCVEESGSAHCVCPMLTCPEANATKVCGSDGVTYGNECQLKTIACRQGLQ
  ISIQSLGPCQEAVAPSTHPTSASVTVTTPGLLLSQALPAPPGALPLAPSSTAHSQTTPPP
  SSRPRTTASVPRTTVWPVLTVPPTAPSPAPSLVASAFGESGSTDGSSDEELSGDQEASGG
  GSGGLEPLEGSSVATPGPPVERASCYNSALGCCSDGKTPSLDAEGSNCPATKVFQGVLEL
  EGVEGQELFYTPEMADPKSELFGETARSIESTLDDLFRNSDVKKDFRSVRLRDLGPGKSV
  RAIVDVHFDPTTAFRAPDVARALLRQIQVSRRRSLGVRRPLQEHVRFMDFDWFPAFITGA
  TSGAIAAGATARATTASRLPSSAVTPRAPHPSHTSQPVAKTTAAPTTRRPPTTAPSRVPG
  RRPPAPQQPPKPCDSQPCFHGGTCQDWALGGGFTCSCPAGRGGAVCEKVLGAPVPAFEGR
  SFLAFPTLRAYHTLRLALEFRALEPQGLLLYNGNARGKDFLALALLDGRVQLRFDTGSGP
  AVLTSAVPVEPGQWHRLELSRHWRRGTLSVDGETPVLGESPSGTDGLNLDTDLFVGGVPE
  DQAAVALERTFVGAGLRGCIRLLDVNNQRLELGIGPGAATRGSGVGECGDHPCLPNPCHG
  GAPCQNLEAGRFHCQCPPGRVGPTCADEKSPCQPNPCHGAAPCRVLPEGGAQCECPLGRE
  GTFCQTASGQDGSGPFLADFNGFSHLELRGLHTFARDLGEKMALEVVFLARGPSGLLLYN
  GQKTDGKGDFVSLALRDRRLEFRYDLGKGAAVIRSREPVTLGAWTRVSLERNGRKGALRV
  GDGPRVLGESPKSRKVPHTVLNLKEPLYVGGAPDFSKLARAAAVSSGFDGAIQLVSLGGR
  QLLTPEHVLRQVDVTSFAGHPCTRASGHPCLNGASCVPREAAYVCLCPGGFSGPHCEKGL
  VEKSAGDVDTLAFDGRTFVEYLNAVTESELANEIPVPETLDSGALHSEKALQSNHFELSL
  RTEATQGLVLWSGKATERADYVALAIVDGHLQLSYNLGSQPVVLRSTVPVNTNRWLRVVA
  HREQREGSLQVGNEAPVTGSSPLGATQLDTDGALWLGGLPELPVGPALPKAYGTGFVGCL
  RDVVVGRHPLHLLEDAVTKPELRPCPTP

• Sequence length: 2068