FMR1

FMR1
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2BKD, 2FMR, 2LA5, 2QND, 4OVA, 4QVZ, 4QW2, 5DE5, 5DE8, 5DEA
Identifikatori
Aliasi	FMR1
Vanjski ID-jevi	OMIM: 309550 MGI: 95564 HomoloGene: 1531 GeneCards: FMR1
Lokacija gena (čovjek)
Hrom.	Hromosom X
Kraj	147,951,125 bp
Lokacija gena (miš)
Hrom.	Hromosom X (miš)
Kraj	67,761,569 bp
Obrazac RNK ekspresije
	; ;
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• protein homodimerization activity; • poly(U) RNA binding; • ribosome binding; • poly(G) binding; • GO:0001948, GO:0016582 vezivanje za proteine; • protein heterodimerization activity; • nucleic acid binding; • translation initiation factor binding; • mRNA binding; • G-quadruplex RNA binding; • RNA strand annealing activity; • siRNA binding; • miRNA binding; • mRNA 3'-UTR binding; • mRNA 5'-UTR binding; • translation repressor activity; • microtubule binding; • chromatin binding; • methylated histone binding; • sequence-specific mRNA binding; • transmembrane transporter binding; • RNA stem-loop binding; • dynein complex binding; • vezivanje sa RNK; • vezivanje identičnih proteina; • translation regulator activity;
Ćelijska komponenta	• citoplazma; • axon terminus; • dendritična kičma; • nukleoplazma; • SMN complex; • mRNA cap binding complex; • dendrit; • Jedarce; • neuron projection; • cytoplasmic ribonucleoprotein granule; • jedro; • polysomal ribosome; • perikaryon; • perinuklearno područje citoplazme; • ribonukleoprotein; • GO:0097483, GO:0097481 postsynaptic density; • chromocenter; • Akson; • međućelijske veze; • neuronal ribonucleoprotein granule; • filopodium tip; • postsynaptic membrane; • polysome; • Cajal body; • hromosom; • growth cone; • Primarno suženje; • growth cone filopodium; • viral replication complex; • ćelijska membrana; • extrinsic component of plasma membrane; • glial cell projection; • projekcija ćelije; • membrana; • dendritic filopodium; • presynaptic membrane; • presynapse; • postsynapse; • sinapsa; • citosol; • messenger ribonucleoprotein complex; • cytoplasmic stress granule; • ribonucleoprotein granule; • soma; • dendritic spine neck; • axon cytoplasm;
Biološki proces	• negative regulation of translational initiation; • regulation of dendritic spine development; • positive regulation of intracellular transport of viral material; • cellular response to virus; • Prerada RNK; • GO:1905616 regulation of gene silencing by miRNA; • cellular response to hydroxyurea; • regulation of neurotransmitter secretion; • GO:1905618 positive regulation of gene silencing by miRNA; • nervous system development; • cellular response to DNA damage stimulus; • Utišavanje gena; • mRNA processing; • mRNA transport; • positive regulation of proteasomal protein catabolic process; • GO:0022415 viral process; • regulation of mRNA stability; • positive regulation of response to DNA damage stimulus; • positive regulation of dendritic spine development; • regulation of filopodium assembly; • negative regulation of cytoplasmic translation; • regulation of translation; • regulation of alternative mRNA splicing, via spliceosome; • regulation of neuronal action potential; • positive regulation of mRNA binding; • cellular response to UV; • modulation by host of viral RNA genome replication; • glutamate receptor signaling pathway; • negative regulation of long-term synaptic depression; • positive regulation of filopodium assembly; • negative regulation of synaptic vesicle exocytosis; • positive regulation of receptor internalization; • negative regulation of voltage-gated calcium channel activity; • positive regulation of translation; • negative regulation of mRNA catabolic process; • GO:0015915 transport; • positive regulation of protein phosphorylation; • central nervous system development; • anterograde axonal transport; • negative regulation of translation; • regulation of dendrite morphogenesis; • regulation of translation at postsynapse, modulating synaptic transmission; • regulation of modification of synaptic structure;
	Izvori:Amigo / QuickGO
Ortolozi
	2332
	14265
	ENSG00000102081
	ENSMUSG00000000838
	Q06787
	P35922
	NM_001185075; NM_001185076; NM_001185081; NM_001185082; NM_002024
	NM_001290424; NM_008031; NM_001374719
	NP_001172004; NP_001172005; NP_001172010; NP_001172011; NP_002015
	n/a
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

FMR1 (gen mentalne retardacije fragilnog X 1) je ljudski gen^[5] koji kodira protein zvani protein mentalne retardacije fragilnog X ili FMRP.^[6] Ovaj protein, koji se najčešće nalazi u mozgu, neophodan je za normalni kognitivni razvoj i reproduktivnu funkciju žena. Mutacije ovog gena mogu izazvati sindrom fragilnog X, intelektualnu invalidnost, prerano otkazivanje jajnika, autizam, Parkisonovu bolest, kašnjenja u razvoju i druge kognitivnne nedostatke.^[7] Premutacija FMR1 vezana je sa spektrom kliničkih fenotpova koji pogađaju više od dva miliona ljudi.^[8]

Funkcija

Plastičnost sinapsi

FMRP ima raznolik niz funkcija u različitim područjima neurona; međutim ove funkcije nisu u potpunosti okarakterizirane. Predloženo je da FMRP ima ulogu u nukleocitoplazmatskoj translaciji iRNK, lokalizaciji dendritske iRNL i sintezu peroteina u sinapsama.^[9] Studije sindoma fragilnog X značajno su pomogle u razumijevanju funkcionalnosti FMRP-a pomoću uočenih efekata gubitka FMRP-a na neurone. Mišji model mentalne retardacije zbog fragilnog X implicirao je dokazao uključenost FMRP-a u plastičnost sinapse..^[10] Sinapsna plastičnost zahtijeva proizvodnju novih proteina, kao odgovor na aktivaciju sinapsnih receptora. Pretpostavlja se da proizvodnja proteina kao odgovor na stimulaciju omogućava trajne fizičke promjene i promijenjene sinapsne veze povezane s procesima učenja i pamćenja.

U plasičnosti sinapsi ovisnoj o FMRP važnu ulogu imao je metabotropni glutamatni receptor 1. grupe signalizacije (mGluR). Post-sinapsna mGluR stimulacija rezultira pojačanom regulacijom sinteze proteina kroz sistem drugog glasnika.^[11] O ulozi mGluR-a u plastičnosti sinapsi dodatno svjedoči promatranje izduženja dendritske bodlje nakon stimulacije.^[12] Nadalje, aktivacija mGluR rezultira sintezom FMRP blizu sinapsi. Proizvedeni FMRP povezuje se sa poliribosomskim kompleksima, nakon stimulacije mGluR-om, eksprimirajući uključivanje proteina mentalne retardacije fragilnog X u procesu translacije. Ovo dalje podržava ulogu FMRP-a u sintezi proteina i rastu sinapsnih veza.^[13] Gubitak FMRP-a rezultira abnormalnim fenotipom dendrita. Konkretno, delecija gena FMR1 u uzorku miševa rezultirala je povećanjem broja sinapsnik kićmi.^[14]

Uloga u translaciji

Predloženi mehanizam efekta FMRP-a na plastičnost sinapsi je kroz njegovu ulogu negativnog regulatora translacije. FMRP je protein koji veže RNK i povezuje se sa poliribosomima.^[13]^[15] > Sposobnosti FMRP-a da vežu za RNK zavise od njegovih KH domena i RGG polja. KH domen je konzervirani motiv, koji karakterizira mnoge RNA-vezujuće proteine. Mutageneza ovog domena rezultirala je poremećenim vezivanjem FMRP-a za RNK.^[16]

Pokazano je da FMRP inhibira translajiju iRNK. Mutacija FMRP proteina rezultirala je nemogućnošću suzbijanja translacije za razliku od divljeg tipa, koji je to mogao učiniti.^[17] Kao što je prethodno pomenuto, stimulacija mGluR povezana je s povećanim nivoom FMRP proteina. Pored toga, stimulacija mGluR rezultira povećanim nivoom FMRP ciljanih iRNK. Studija je pokazala da su bazni nivoi proteina kodirani ovim ciljnim iRNK značajno povišeni i nepravilno regulirani kod miševa s nedostatkom FMRP-a .^[18]

Represija pri translaciji FMRP djeluje tako što inhibira pokretanje translacije. FMRP izravno veže CYFIP1, što zauzvrat veže faktor inicijacije prevođenja eIF4E. Kompleks FMRP-CYFIP1 sprečava inicijaciju ovisnu o eIF4E, djelujući tako na represiju translacije.^[19] Kada se primijeni na uočeni fenotip kod sindroma fragilnog X, višak nivoa proteina i smanjenje translaciijke kontrole mogu se objasniti gubitkom represije translacije FMRP-om kod sinroma fragilnog X.^[19]^[20] FMRP deluje na kontrolu translacije velike grupe ciljnih iRNK; međutim opseg translacijske kontrole FMRP-a je nepoznat. Pokazalo se da protein potiskuje prevođenje ciljanih iRNK u sinapsama, uključujući one koji kodiraju citoskeletne proteine Arc / Arg3.1 i MAP1B, te CaM kinazu II.^[21] Pored toga, FMRP veže PSD-95 i GluR1/2 iRNK. Važno je da ove FMRP-vezujuće iRNK imaju značajnu ulogu u plastičnosti neurona.

Pokazalo se da je translacijska kontrola FMRP regulirana mGluR-signalizacijom. Stimulacija mGluR može rezultirati transportom iRNK kompleksa u sinapse za lokalnu sintezu proteina. Pritom se FMRP granule lokaliziraju sa MAP1B iRNK i rRNK u dendritima, što sugerira da će ovaj kompleks u cjelini možda trebati transportirati u dendrite za lokalnu sintezu proteina. Pored toga, utvrđeno je da su za mGluR-zavisnu translokaciju FMRP-a u dendrite neophodne i mikrotubule

FMRP može imati dodatnu ulogu u lokalnoj sintezi proteina, pomažući u povezivanju tereta iRNK i mikrotubula.^[22] Dakle, FMRP je u stanju da reguliše efikasnost transporta, kao i potiskivanje prevođenja tokom transporta. Konačno, FMRP sinteza, ubikvitinacija i proteoliza brzo se javljaju kao odgovor na mGluR signalizaciju, što sugerira izuzetno dinamičnu ulogu translacijskog regulatora.

Ekspresija gena

Gen FMR1 nalazi se na X hromosomu i sadrži ponavljajući CGG trinukleotid. Kod većine ljudi, segment CGG se ponovi približno 5-44 puta. Veći broj ponavljajućih segmenta CGG povezan je sa oštećenom kognitivnom i reproduktivnom funkcijom. Ako osoba ima 45-54 ponavljanja, to se smatra "sivom zonom" ili graničnim rizikom, 55-200 ponavljanja naziva se predmutacijom, a više od 200 ponavljanja – punom mutacijom gena FMR1, prema Američkom koledžu za medicinsku genetiku i genomiku.^[23] Prva kompletna sekvence ponavljajućeg širenja DNK kod nekoga sa potpunom mutacijom dobijena je 2012., pomoću SMART sekvenciranja.^[24] Ovo je primjer poremećaja ponavljanja trinukleotida. Ekspanzija trinukleotidnog ponavljanja vjerovatno je posljedica proklizavanja niti tokom popravki ili replikacije DNK.^[25]

FMR1 je protein koji veže hromatin i funkcionira u odgovoru na oštećenje DNK.^[26]^[27] FMR1 zauzima mjesta na mejotskm hromosomu i regulira dinamiku mehanizama odgovora na oštećenje DNK tokom sperspermatogeneze.

Gen FMR1 nalazi se na dugom (q) kraku X hromosoma, na položaju 27.3, od baznog para 146,699.054 do para 146,738.156

Vezane promjene

Sindrom fragilnog X

Gotovo svi slučajevi sindroma fragilnog X-a su uzrokovani ekspanzijom CGG trinukleotidnog ponavljanja u genu FMR1. U tim slučajevima, CGG se abnormalno ponavlja od 200 do više od 1.000 puta. Kao rezultat, ovaj dio gena FMR1 je metiliran, što utišava gen (isključen je i ne stvara nikakve proteine). Bez odgovarajućeg FMR1, mogu se razviti teške smetnje u učenju ili intelektualne smetnje, zajedno sa fizičkim abnormalnostima.

Manje od 1% svih slučajeva sindroma fragilnog X uzrokuju mutacije koji deletiraju dio ili cijeli gen FMR1 ili mijenjaju bazni par, što dovodi do promjene jedne od mutiranih aminokiselina u genu (tačkasta mutacija). Ove mutacije remete trodimenzijski oblik FMRP-a ili sprečavaju sintezu proteina, što dovodi do znakova i simptomansindroma fragilnog X .

Sekvenca CGG u genu FMR1 koja se ponavlja između 55 i 200 puta opisana je kao predmutacija. Iako je većina osoba s premutacijom intelektualno normalna, neke od njih imaju blage verzije fizičkih karakteristika koje se vide kod sindroma krhkog X (poput istaknutih ušiju), a mogu imati i mentalnih problema, poput anksioznosti ili depresije.

Sindrom X-vezane tremor / sindrom ataksije

Premutacije su povezane sa povećanim rizikom od sidroma X-fragilno vezanog tremora ataksije (FXTAS). FXTAS karakteriziraju ataksija (gubitak koordinacije), tremor, gubitak pamćenja, gubitak osjećaja u donjim ekstremitetima (periferna neuropatija) i mentalne i promjene ponašanja. Poremećaj se obično razvija kasno u životu.

Prerano starenje jajnika

Gen FMR1 ima vrlo važnu ulogu u funkciji jajnika, neovisno o kognitivnim/nervnim efektima. Manja proširenja ponavljanja CGG koja ne uzrokuju sindrom fragilnog X povezani su s povećanim rizikom za prerano starenje jajnika, koji se naziva i okultnom primarnom insuficijencijom jajnika, stanjem u kojem žene prerano iscrpljuju funkciju jajnika.^[28]^[29]^[30]

Sindrom policistnih jajnika

Utvrđeno je da je vrlo specifičan pod-genotip FMR1 povezan sa sindromom višecistnih jajnika (PCOS). Ekspresija gena, koja se naziva heterozigotno-normalna/niska, može prouzrokovati prekomjernu aktivnost folikula nalik PCOS-u i hiperaktivnu funkciju jajnika mlađih žena.

Interakcije

Pokazano je da FMR1 ima interakcije sa:

Reference

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Dopunska literatura

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