OTOF
Otoferlin jest protein koji je kod ljudi kodiran genom OTOF sa hromosoma 2.[5][6][7]
Amiokiselininska sekvenca
urediDužina polipeptidnog lanca je 1.997 aminokiselina, a molkekulska težina 226.753 Da.[8]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MALLIHLKTV | SELRGRGDRI | AKVTFRGQSF | YSRVLENCED | VADFDETFRW | ||||
| PVASSIDRNE | MLEIQVFNYS | KVFSNKLIGT | FRMVLQKVVE | ESHVEVTDTL | ||||
| IDDNNAIIKT | SLCVEVRYQA | TDGTVGSWDD | GDFLGDESLQ | EEEKDSQETD | ||||
| GLLPGSRPSS | RPPGEKSFRR | AGRSVFSAMK | LGKNRSHKEE | PQRPDEPAVL | ||||
| EMEDLDHLAI | RLGDGLDPDS | VSLASVTALT | TNVSNKRSKP | DIKMEPSAGR | ||||
| PMDYQVSITV | IEARQLVGLN | MDPVVCVEVG | DDKKYTSMKE | STNCPYYNEY | ||||
| FVFDFHVSPD | VMFDKIIKIS | VIHSKNLLRS | GTLVGSFKMD | VGTVYSQPEH | ||||
| QFHHKWAILS | DPDDISSGLK | GYVKCDVAVV | GKGDNIKTPH | KANETDEDDI | ||||
| EGNLLLPEGV | PPERQWARFY | VKIYRAEGLP | RMNTSLMANV | KKAFIGENKD | ||||
| LVDPYVQVFF | AGQKGKTSVQ | KSSYEPLWNE | QVVFTDLFPP | LCKRMKVQIR | ||||
| DSDKVNDVAI | GTHFIDLRKI | SNDGDKGFLP | TLGPAWVNMY | GSTRNYTLLD | ||||
| EHQDLNEGLG | EGVSFRARLL | LGLAVEIVDT | SNPELTSSTE | VQVEQATPIS | ||||
| ESCAGKMEEF | FLFGAFLEAS | MIDRRNGDKP | ITFEVTIGNY | GNEVDGLSRP | ||||
| QRPRPRKEPG | DEEEVDLIQN | ASDDEAGDAG | DLASVSSTPP | MRPQVTDRNY | ||||
| FHLPYLERKP | CIYIKSWWPD | QRRRLYNANI | MDHIADKLEE | GLNDIQEMIK | ||||
| TEKSYPERRL | RGVLEELSCG | CCRFLSLADK | DQGHSSRTRL | DRERLKSCMR | ||||
| ELENMGQQAR | MLRAQVKRHT | VRDKLRLCQN | FLQKLRFLAD | EPQHSIPDIF | ||||
| IWMMSNNKRV | AYARVPSKDL | LFSIVEEETG | KDCAKVKTLF | LKLPGKRGFG | ||||
| SAGWTVQAKV | ELYLWLGLSK | QRKEFLCGLP | CGFQEVKAAQ | GLGLHAFPPV | ||||
| SLVYTKKQAF | QLRAHMYQAR | SLFAADSSGL | SDPFARVFFI | NQSQCTEVLN | ||||
| ETLCPTWDQM | LVFDNLELYG | EAHELRDDPP | IIVIEIYDQD | SMGKADFMGR | ||||
| TFAKPLVKMA | DEAYCPPRFP | PQLEYYQIYR | GNATAGDLLA | AFELLQIGPA | ||||
| GKADLPPING | PVDVDRGPIM | PVPMGIRPVL | SKYRVEVLFW | GLRDLKRVNL | ||||
| AQVDRPRVDI | ECAGKGVQSS | LIHNYKKNPN | FNTLVKWFEV | DLPENELLHP | ||||
| PLNIRVVDCR | AFGRYTLVGS | HAVSSLRRFI | YRPPDRSAPS | WNTTVRLLRR | ||||
| CRVLCNGGSS | SHSTGEVVVT | MEPEVPIKKL | ETMVKLDATS | EAVVKVDVAE | ||||
| EEKEKKKKKK | GTAEEPEEEE | PDESMLDWWS | KYFASIDTMK | EQLRQQEPSG | ||||
| IDLEEKEEVD | NTEGLKGSMK | GKEKARAAKE | EKKKKTQSSG | SGQGSEAPEK | ||||
| KKPKIDELKV | YPKELESEFD | NFEDWLHTFN | LLRGKTGDDE | DGSTEEERIV | ||||
| GRFKGSLCVY | KVPLPEDVSR | EAGYDSTYGM | FQGIPSNDPI | NVLVRVYVVR | ||||
| ATDLHPADIN | GKADPYIAIR | LGKTDIRDKE | NYISKQLNPV | FGKSFDIEAS | ||||
| FPMESMLTVA | VYDWDLVGTD | DLIGETKIDL | ENRFYSKHRA | TCGIAQTYST | ||||
| HGYNIWRDPM | KPSQILTRLC | KDGKVDGPHF | GPPGRVKVAN | RVFTGPSEIE | ||||
| DENGQRKPTD | EHVALLALRH | WEDIPRAGCR | LVPEHVETRP | LLNPDKPGIE | ||||
| QGRLELWVDM | FPMDMPAPGT | PLDISPRKPK | KYELRVIIWN | TDEVVLEDDD | ||||
| FFTGEKSSDI | FVRGWLKGQQ | EDKQDTDVHY | HSLTGEGNFN | WRYLFPFDYL | ||||
| AAEEKIVISK | KESMFSWDET | EYKIPARLTL | QIWDADHFSA | DDFLGAIELD | ||||
| LNRFPRGAKT | AKQCTMEMAT | GEVDVPLVSI | FKQKRVKGWW | PLLARNENDE | ||||
| FELTGKVEAE | LHLLTAEEAE | KNPVGLARNE | PDPLEKPNRP | DTSFIWFLNP | ||||
| LKSARYFLWH | TYRWLLLKLL | LLLLLLLLLA | LFLYSVPGYL | VKKILGA |
Funkcija
urediMutacije u ovom genu uzrok su neurosenzorne nesindromske recesivna gluhoće, DFNB9. Kratki oblik kodiranog proteina ima tri C2 domena, jedan karboksi-terminal, transmembranski domen koji se nalazi iu faktoru spermatogeneze C. elegans FER-1 i ljudskom disferlinu, dok duga obrazac ima šest C2 domena. Homologni proteini otoferlina kod ljudi za koje se pokazalo da su povezani s ljudskim bolestima su disferlin i mioferlin. I disferlin i mioferlin imaju po sedam C2 domena. C2A u dužem obliku otoferlina sa šest C2 domena je strukturno sličan disferlinu C2A. Međutim, petlja 1 na mjestu vezivanja za kalcij otoferlina C2A je značajno kraća od homologne petlje u domenima disferlina i mioferlina C2A. Zbog toga se ne može vezati za kalcij. Otoferlin C2A također nije u stanju da se veže za fosfolipide i stoga je strukturno i funkcionalno drugačiji od drugih C2 domena.[9] Homologija sugerira da ovaj protein može biti uključen u fuziju vezikulske membrane. Slično disferlinu i mioferlinu, otoferlin ima FerA domen i pokazalo se da njegov FerA domen stupa u interakciju sa blizanci-ionskim lipidima na način ovisan o kalciju i s negativno nabijenim lipidima na način koji ne ovisi o kalciju.[10] Procijenjeni naboj FerA domena među proteinima ferlina značajno varira. Na pH 7, procijenjeni naboj disferlina je –8,4 dok je otoferlin FerA +8,5.[10] Za ovaj gen nađeno je nekoliko varijanti transkripta koje kodiraju više izoformi.[7]
Reference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000115155 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062372 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Yasunaga S, Grati M, Cohen-Salmon M, El-Amraoui A, Mustapha M, Salem N, El-Zir E, Loiselet J, Petit C (april 1999). "A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness". Nature Genetics. 21 (4): 363–9. doi:10.1038/7693. PMID 10192385. S2CID 19269361.
- ^ Rodríguez-Ballesteros M, Reynoso R, Olarte M, Villamar M, Morera C, Santarelli R, Arslan E, Medá C, Curet C, Völter C, Sainz-Quevedo M, Castorina P, Ambrosetti U, Berrettini S, Frei K, Tedín S, Smith J, Cruz Tapia M, Cavallé L, Gelvez N, Primignani P, Gómez-Rosas E, Martín M, Moreno-Pelayo MA, Tamayo M, Moreno-Barral J, Moreno F, del Castillo I (juni 2008). "A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy". Human Mutation. 29 (6): 823–31. doi:10.1002/humu.20708. PMID 18381613. S2CID 19170712.
- ^ a b "Entrez Gene: OTOF otoferlin".
- ^ "UniProt, Q9HC10" (jezik: engleski). Pristupljeno 14. 11. 2021.
- ^ Helfmann S, Neumann P, Tittmann K, Moser T, Ficner R, Reisinger E (februar 2011). "The crystal structure of the C₂A domain of otoferlin reveals an unconventional top loop region". Journal of Molecular Biology. 406 (3): 479–90. doi:10.1016/j.jmb.2010.12.031. PMID 21216247.
- ^ a b Harsini FM, Chebrolu S, Fuson KL, White MA, Rice AM, Sutton RB (juli 2018). "FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins". Scientific Reports. 8 (1): 10949. doi:10.1038/s41598-018-29184-1. PMC 6053371. PMID 30026467.
Dopunska literatura
uredi- Fukushima K, Ramesh A, Srisailapathy CR, Ni L, Wayne S, O'Neill ME, Van Camp G, Coucke P, Jain P, Wilcox ER, Smith SD, Kenyon JB, Zbar RI, Smith RJ (oktobar 1995). "An autosomal recessive nonsyndromic form of sensorineural hearing loss maps to 3p-DFNB6". Genome Research. 5 (3): 305–8. doi:10.1101/gr.5.3.305. PMID 8593615.
- Yasunaga S, Petit C (maj 2000). "Physical map of the region surrounding the OTOFERLIN locus on chromosome 2p22-p23". Genomics. 66 (1): 110–2. doi:10.1006/geno.2000.6185. PMID 10843812.
- Adato A, Raskin L, Petit C, Bonne-Tamir B (juni 2000). "Deafness heterogeneity in a Druze isolate from the Middle East: novel OTOF and PDS mutations, low prevalence of GJB2 35delG mutation and indication for a new DFNB locus". European Journal of Human Genetics. 8 (6): 437–42. doi:10.1038/sj.ejhg.5200489. PMID 10878664.
- Yasunaga S, Grati M, Chardenoux S, Smith TN, Friedman TB, Lalwani AK, Wilcox ER, Petit C (septembar 2000). "OTOF encodes multiple long and short isoforms: genetic evidence that the long ones underlie recessive deafness DFNB9". American Journal of Human Genetics. 67 (3): 591–600. doi:10.1086/303049. PMC 1287519. PMID 10903124.
- Migliosi V, Modamio-Høybjør S, Moreno-Pelayo MA, Rodríguez-Ballesteros M, Villamar M, Tellería D, Menéndez I, Moreno F, Del Castillo I (juli 2002). "Q829X, a novel mutation in the gene encoding otoferlin (OTOF), is frequently found in Spanish patients with prelingual non-syndromic hearing loss". Journal of Medical Genetics. 39 (7): 502–6. doi:10.1136/jmg.39.7.502. PMC 1735186. PMID 12114484.
- Mirghomizadeh F, Pfister M, Apaydin F, Petit C, Kupka S, Pusch CM, Zenner HP, Blin N (juli 2002). "Substitutions in the conserved C2C domain of otoferlin cause DFNB9, a form of nonsyndromic autosomal recessive deafness". Neurobiology of Disease. 10 (2): 157–64. doi:10.1006/nbdi.2002.0488. PMID 12127154. S2CID 37646982.
- Mirghomizadeh F, Pfister M, Blin N, Pusch CM (januar 2003). "Uncommon cytidine-homopolymer dimorphism in 5'-UTR of the human otoferlin gene". International Journal of Molecular Medicine. 11 (1): 63–4. doi:10.3892/ijmm.11.1.63. PMID 12469219.
- Varga R, Kelley PM, Keats BJ, Starr A, Leal SM, Cohn E, Kimberling WJ (januar 2003). "Non-syndromic recessive auditory neuropathy is the result of mutations in the otoferlin (OTOF) gene". Journal of Medical Genetics. 40 (1): 45–50. doi:10.1136/jmg.40.1.45. PMC 1735255. PMID 12525542.
- Piechotta K, Garbarini N, England R, Delpire E (decembar 2003). "Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- cotransporter in the nervous system: evidence for a scaffolding role of the kinase". The Journal of Biological Chemistry. 278 (52): 52848–56. doi:10.1074/jbc.M309436200. PMID 14563843.
- Varga R, Avenarius MR, Kelley PM, Keats BJ, Berlin CI, Hood LJ, Morlet TG, Brashears SM, Starr A, Cohn ES, Smith RJ, Kimberling WJ (juli 2006). "OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele". Journal of Medical Genetics. 43 (7): 576–81. doi:10.1136/jmg.2005.038612. PMC 2593030. PMID 16371502.
- Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M, Rostaing P, Hamard G, Triller A, Avan P, Moser T, Petit C (oktobar 2006). "Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse". Cell. 127 (2): 277–89. doi:10.1016/j.cell.2006.08.040. PMID 17055430. S2CID 15233556.