RBCC Red Blood Cell Collection

OPTN (FIP2, GLC1E, HIP7, HYPL, NRP) [Confidence: low (only semi-automatic identification from reviews)]
Optineurin (E3-14.7K-interacting protein; FIP-2; Huntingtin yeast partner L; Huntingtin-interacting protein 7; HIP-7; Huntingtin-interacting protein L; NEMO-related protein; Optic neuropathy-inducing protein; Transcription factor IIIA-interacting protein; TFIIIA-IntP)

UniProt Q96CV9
ID OPTN_HUMAN Reviewed; 577 AA.
AC Q96CV9; B3KP00; D3DRS4; D3DRS8; Q5T672; Q5T673; Q5T674; Q5T675;
read moreAC Q7LDL9; Q8N562; Q9UET9; Q9UEV4; Q9Y218;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 11-JAN-2011, sequence version 2.
DT 22-JAN-2014, entry version 97.
DE RecName: Full=Optineurin;
DE AltName: Full=E3-14.7K-interacting protein;
DE AltName: Full=FIP-2;
DE AltName: Full=Huntingtin yeast partner L;
DE AltName: Full=Huntingtin-interacting protein 7;
DE Short=HIP-7;
DE AltName: Full=Huntingtin-interacting protein L;
DE AltName: Full=NEMO-related protein;
DE AltName: Full=Optic neuropathy-inducing protein;
DE AltName: Full=Transcription factor IIIA-interacting protein;
DE Short=TFIIIA-IntP;
GN Name=OPTN; Synonyms=FIP2, GLC1E, HIP7, HYPL, NRP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 3), VARIANTS
RP SER-201; HIS-213; ARG-216; GLU-322 AND PRO-357, SUBCELLULAR LOCATION,
RP TISSUE SPECIFICITY, INDUCTION, AND INTERACTION WITH ADENOVIRUS E3.
RC TISSUE=Cervix carcinoma;
RX PubMed=9488477;
RA Li Y., Kang J., Horwitz M.S.;
RT "Interaction of an adenovirus E3 14.7-kilodalton protein with a novel
RT tumor necrosis factor alpha-inducible cellular protein containing
RT leucine zipper domains.";
RL Mol. Cell. Biol. 18:1601-1610(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, VARIANTS GLC1E LYS-50 AND GLN-545, AND
RP VARIANTS LYS-98; SER-201; HIS-213; ARG-216; GLU-322 AND PRO-357.
RC TISSUE=Trabecular meshwork;
RX PubMed=11834836; DOI=10.1126/science.1066901;
RA Rezaie T., Child A., Hitchings R., Brice G., Miller L.,
RA Coca-Prados M., Heon E., Krupin T., Ritch R., Kreutzer D., Crick R.P.,
RA Sarfarazi M.;
RT "Adult-onset primary open-angle glaucoma caused by mutations in
RT optineurin.";
RL Science 295:1077-1079(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-201; HIS-213;
RP ARG-216; GLU-322 AND PRO-357.
RA Li D., Roberts R.;
RT "Human FIP-2: genomic structure and mutational analysis in ARVD
RT patients.";
RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-322.
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT GLU-322.
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP GLU-322.
RC TISSUE=Cervix, and Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 412-555, AND INTERACTION WITH HD.
RC TISSUE=Testis;
RX PubMed=9700202; DOI=10.1093/hmg/7.9.1463;
RA Faber P.W., Barnes G.T., Srinidhi J., Chen J., Gusella J.F.,
RA MacDonald M.E.;
RT "Huntingtin interacts with a family of WW domain proteins.";
RL Hum. Mol. Genet. 7:1463-1474(1998).
RN [9]
RP INTERACTION WITH HD AND RAB8.
RX PubMed=11137014; DOI=10.1016/S0960-9822(00)00864-2;
RA Hattula K., Peraenen J.;
RT "FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates
RT cellular morphogenesis.";
RL Curr. Biol. 10:1603-1606(2000).
RN [10]
RP SUBCELLULAR LOCATION, INDUCTION, AND PHOSPHORYLATION.
RX PubMed=10807909; DOI=10.1074/jbc.M001500200;
RA Schwamborn K., Weil R., Courtois G., Whiteside S.T., Israeel A.;
RT "Phorbol esters and cytokines regulate the expression of the NEMO-
RT related protein, a molecule involved in a NF-kappa B-independent
RT pathway.";
RL J. Biol. Chem. 275:22780-22789(2000).
RN [11]
RP INTERACTION WITH GTF3A.
RX PubMed=10756201; DOI=10.1093/nar/28.9.1986;
RA Moreland R.J., Dresser M.E., Rodgers J.S., Roe B.A., Conaway J.W.,
RA Conaway R.C., Hanas J.S.;
RT "Identification of a transcription factor IIIA-interacting protein.";
RL Nucleic Acids Res. 28:1986-1993(2000).
RN [12]
RP INDUCTION.
RX PubMed=12379221; DOI=10.1016/S0006-291X(02)02395-1;
RA Vittitow J., Borras T.;
RT "Expression of optineurin, a glaucoma-linked gene, is influenced by
RT elevated intraocular pressure.";
RL Biochem. Biophys. Res. Commun. 298:67-74(2002).
RN [13]
RP INDUCTION.
RX PubMed=12646749; DOI=10.1159/000069133;
RA Kamphuis W., Schneemann A.;
RT "Optineurin gene expression level in human trabecular meshwork does
RT not change in response to pressure elevation.";
RL Ophthalmic Res. 35:93-96(2003).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MYO6 AND RAB8.
RX PubMed=15837803; DOI=10.1083/jcb.200501162;
RA Sahlender D.A., Roberts R.C., Arden S.D., Spudich G., Taylor M.J.,
RA Luzio J.P., Kendrick-Jones J., Buss F.;
RT "Optineurin links myosin VI to the Golgi complex and is involved in
RT Golgi organization and exocytosis.";
RL J. Cell Biol. 169:285-295(2005).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, INDUCTION, INTERACTION WITH TBK1 AND
RP TRAF3, UBIQUITIN-BINDING MOTIF, AND MUTAGENESIS OF ASP-474.
RX PubMed=20174559; DOI=10.1371/journal.ppat.1000778;
RA Mankouri J., Fragkoudis R., Richards K.H., Wetherill L.F., Harris M.,
RA Kohl A., Elliott R.M., Macdonald A.;
RT "Optineurin negatively regulates the induction of IFNbeta in response
RT to RNA virus infection.";
RL PLoS Pathog. 6:E1000778-E1000778(2010).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [21]
RP VARIANT LYS-98.
RX PubMed=14627677; DOI=10.1136/jmg.40.11.842;
RA Melki R., Belmouden A., Akhayat O., Brezin A., Garchon H.-J.;
RT "The M98K variant of the OPTINEURIN (OPTN) gene modifies initial
RT intraocular pressure in patients with primary open angle glaucoma.";
RL J. Med. Genet. 40:842-844(2003).
RN [22]
RP VARIANTS GLC1E ASP-103 AND ARG-486.
RX PubMed=12939304; DOI=10.1167/iovs.02-0693;
RA Leung Y.F., Fan B.J., Lam D.S.C., Lee W.S., Tam P.O.S., Chua J.K.H.,
RA Tham C.C.Y., Lai J.S.M., Fan D.S.P., Pang C.P.;
RT "Different optineurin mutation pattern in primary open-angle
RT glaucoma.";
RL Invest. Ophthalmol. Vis. Sci. 44:3880-3884(2003).
RN [23]
RP VARIANT GLC1E GLN-545.
RX PubMed=14597044; DOI=10.1016/S0002-9394(03)00577-4;
RA Alward W.L.M., Kwon Y.H., Kawase K., Craig J.E., Hayreh S.S.,
RA Johnson A.T., Khanna C.L., Yamamoto T., Mackey D.A., Roos B.R.,
RA Affatigato L.M., Sheffield V.C., Stone E.M.;
RT "Evaluation of optineurin sequence variations in 1,048 patients with
RT open-angle glaucoma.";
RL Am. J. Ophthalmol. 136:904-910(2003).
RN [24]
RP VARIANT LYS-98.
RX PubMed=15498064; DOI=10.1111/j.1442-9071.2004.00886.x;
RA Baird P.N., Richardson A.J., Craig J.E., Mackey D.A., Rochtchina E.,
RA Mitchell P.;
RT "Analysis of optineurin (OPTN) gene mutations in subjects with and
RT without glaucoma: the blue mountains eye study.";
RL Clin. Exp. Ophthalmol. 32:518-522(2004).
RN [25]
RP VARIANT GLC1E ARG-486.
RX PubMed=15326130; DOI=10.1167/iovs.04-0107;
RA Willoughby C.E., Chan L.L.Y., Herd S., Billingsley G., Noordeh N.,
RA Levin A.V., Buys Y., Trope G., Sarfarazi M., Heon E.;
RT "Defining the pathogenicity of optineurin in juvenile open-angle
RT glaucoma.";
RL Invest. Ophthalmol. Vis. Sci. 45:3122-3130(2004).
RN [26]
RP VARIANTS GLC1E ASP-26 AND GLN-545, AND VARIANT LYS-98.
RX PubMed=15557444; DOI=10.1167/iovs.03-1403;
RA Funayama T., Ishikawa K., Ohtake Y., Tanino T., Kurosaka D.,
RA Kimura I., Suzuki K., Ideta H., Nakamoto K., Yasuda N., Fujimaki T.,
RA Murakami A., Asaoka R., Hotta Y., Tanihara H., Kanamoto T.,
RA Mishima H., Fukuchi T., Abe H., Iwata T., Shimada N., Kudoh J.,
RA Shimizu N., Mashima Y.;
RT "Variants in optineurin gene and their association with tumor necrosis
RT factor-alpha polymorphisms in Japanese patients with glaucoma.";
RL Invest. Ophthalmol. Vis. Sci. 45:4359-4367(2004).
RN [27]
RP VARIANT GLC1E ASP-26.
RX PubMed=15226658; DOI=10.1097/00061198-200408000-00007;
RA Fuse N., Takahashi K., Akiyama H., Nakazawa T., Seimiya M.,
RA Kuwahara S., Tamai M.;
RT "Molecular genetic analysis of optineurin gene for primary open-angle
RT and normal tension glaucoma in the Japanese population.";
RL J. Glaucoma 13:299-303(2004).
RN [28]
RP VARIANT NPG ASP-26.
RX PubMed=15370540; DOI=10.1080/13816810490514298;
RA Umeda T., Matsuo T., Nagayama M., Tamura N., Tanabe Y., Ohtsuki H.;
RT "Clinical relevance of optineurin sequence alterations in Japanese
RT glaucoma patients.";
RL Ophthalmic Genet. 25:91-99(2004).
RN [29]
RP VARIANT ALS12 GLY-478, AND SUBCELLULAR LOCATION.
RX PubMed=20428114; DOI=10.1038/nature08971;
RA Maruyama H., Morino H., Ito H., Izumi Y., Kato H., Watanabe Y.,
RA Kinoshita Y., Kamada M., Nodera H., Suzuki H., Komure O., Matsuura S.,
RA Kobatake K., Morimoto N., Abe K., Suzuki N., Aoki M., Kawata A.,
RA Hirai T., Kato T., Ogasawara K., Hirano A., Takumi T., Kusaka H.,
RA Hagiwara K., Kaji R., Kawakami H.;
RT "Mutations of optineurin in amyotrophic lateral sclerosis.";
RL Nature 465:223-226(2010).
RN [30]
RP PHOSPHORYLATION AT SER-177 BY TBK1.
RX PubMed=21617041; DOI=10.1126/science.1205405;
RA Wild P., Farhan H., McEwan D.G., Wagner S., Rogov V.V., Brady N.R.,
RA Richter B., Korac J., Waidmann O., Choudhary C., Dotsch V., Bumann D.,
RA Dikic I.;
RT "Phosphorylation of the autophagy receptor optineurin restricts
RT Salmonella growth.";
RL Science 333:228-233(2011).
CC -!- FUNCTION: Plays an important role in the maintenance of the Golgi
CC complex, in membrane trafficking, in exocytosis, through its
CC interaction with myosin VI and Rab8. Links myosin VI to the Golgi
CC complex and plays an important role in Golgi ribbon formation.
CC Negatively regulates the induction of IFNB in response to RNA
CC virus infection. Plays a neuroprotective role in the eye and optic
CC nerve. Probably part of the TNF-alpha signaling pathway that can
CC shift the equilibrium toward induction of cell death. May act by
CC regulating membrane trafficking and cellular morphogenesis via a
CC complex that contains Rab8 and hungtingtin (HD). May constitute a
CC cellular target for adenovirus E3 14.7, an inhibitor of TNF-alpha
CC functions, thereby affecting cell death.
CC -!- SUBUNIT: Interacts with E3 14.7 kDa protein of group C human
CC adenovirus. Interacts with HD. Interacts with Rab8 (RAB8A and/or
CC RAB8B). Interacts with transcription factor IIIA (GTF3A).
CC Interacts with TRAF3, TBK1 and MYO6. Binds to ubiquitin.
CC -!- INTERACTION:
CC Q99IB8:- (xeno); NbExp=3; IntAct=EBI-748974, EBI-6858501;
CC Q13023:AKAP6; NbExp=2; IntAct=EBI-748974, EBI-1056102;
CC Q03001:DST; NbExp=2; IntAct=EBI-748974, EBI-310758;
CC O75923:DYSF; NbExp=3; IntAct=EBI-748974, EBI-2799016;
CC Q00013:MPP1; NbExp=2; IntAct=EBI-748974, EBI-711788;
CC P20929:NEB; NbExp=3; IntAct=EBI-748974, EBI-1049657;
CC Q14BN4:SLMAP; NbExp=2; IntAct=EBI-748974, EBI-1043216;
CC Q9UNH7:SNX6; NbExp=2; IntAct=EBI-748974, EBI-949294;
CC Q9UHD2:TBK1; NbExp=11; IntAct=EBI-748974, EBI-356402;
CC Q15025:TNIP1; NbExp=3; IntAct=EBI-748974, EBI-357849;
CC Q8WZ42:TTN; NbExp=2; IntAct=EBI-748974, EBI-681210;
CC P04275:VWF; NbExp=2; IntAct=EBI-748974, EBI-981819;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region. Golgi
CC apparatus. Golgi apparatus, trans-Golgi network. Note=Found in the
CC perinuclear region and associates with the Golgi apparatus.
CC Colocalizes with MYO6 and RAB8 at the Golgi complex and in
CC vesicular structures close to the plasma membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q96CV9-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q96CV9-2; Sequence=VSP_013262;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q96CV9-3; Sequence=VSP_013261;
CC -!- TISSUE SPECIFICITY: Present in aqueous humor of the eye (at
CC protein level). Highly expressed in trabecular meshwork. Expressed
CC nonpigmented ciliary epithelium, retina, brain, adrenal cortex,
CC fetus, lymphocyte, fibroblast, skeletal muscle, heart, liver,
CC brain and placenta.
CC -!- INDUCTION: Upon TNF and interferon treatments. Up-regulated in
CC direct response to viral infection.
CC -!- DOMAIN: Ubiquitin-binding motif (UBAN) is essential for its
CC inhibitory function, subcellular localization and interaction with
CC TBK1.
CC -!- PTM: Phosphorylated by TBK1, leading to restrict bacterial
CC proliferation in case of infection. Phosphorylation is induced by
CC phorbol esters and decreases its half-time.
CC -!- DISEASE: Glaucoma 1, open angle, E (GLC1E) [MIM:137760]: A form of
CC primary open angle glaucoma (POAG). POAG is characterized by a
CC specific pattern of optic nerve and visual field defects. The
CC angle of the anterior chamber of the eye is open, and usually the
CC intraocular pressure is increased. However, glaucoma can occur at
CC any intraocular pressure. The disease is generally asymptomatic
CC until the late stages, by which time significant and irreversible
CC optic nerve damage has already taken place. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Glaucoma, normal pressure (NPG) [MIM:606657]: A primary
CC glaucoma characterized by intraocular pression consistently within
CC the statistically normal population range. Note=Disease
CC susceptibility is associated with variations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis 12 (ALS12) [MIM:613435]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- CAUTION: According to some authors (PubMed:12379221) its
CC expression is regulated by intraocular pressure, suggesting a
CC protective role in case of high pressure, while according to other
CC authors (PubMed:12646749), it is not up-regulated in response to
CC pressure elevation.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAI16552.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/OPTN";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF061034; AAC16046.1; -; mRNA.
DR EMBL; AF061034; AAC16047.1; -; mRNA.
DR EMBL; AF420371; AAL76327.1; -; mRNA.
DR EMBL; AF420372; AAL76328.1; -; mRNA.
DR EMBL; AF420373; AAL76329.1; -; mRNA.
DR EMBL; AF283527; AAG00497.1; -; Genomic_DNA.
DR EMBL; AF283520; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AF283521; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AF283522; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AF283523; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AF283524; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AF283525; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AF283526; AAG00497.1; JOINED; Genomic_DNA.
DR EMBL; AK055403; BAG51512.1; -; mRNA.
DR EMBL; AL355355; CAI16549.1; -; Genomic_DNA.
DR EMBL; AL355355; CAI16550.1; -; Genomic_DNA.
DR EMBL; AL355355; CAI16551.1; -; Genomic_DNA.
DR EMBL; AL355355; CAI16552.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471072; EAW86301.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86302.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86303.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86304.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86306.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86308.1; -; Genomic_DNA.
DR EMBL; CH471072; EAW86309.1; -; Genomic_DNA.
DR EMBL; BC013876; AAH13876.1; -; mRNA.
DR EMBL; BC032762; AAH32762.1; -; mRNA.
DR EMBL; AF049614; AAC26850.1; -; mRNA.
DR RefSeq; NP_001008212.1; NM_001008211.1.
DR RefSeq; NP_001008213.1; NM_001008212.1.
DR RefSeq; NP_001008214.1; NM_001008213.1.
DR RefSeq; NP_068815.2; NM_021980.4.
DR RefSeq; XP_005252392.1; XM_005252335.1.
DR RefSeq; XP_005252393.1; XM_005252336.1.
DR RefSeq; XP_005252394.1; XM_005252337.1.
DR RefSeq; XP_005252395.1; XM_005252338.1.
DR UniGene; Hs.332706; -.
DR PDB; 2LO4; NMR; -; A=550-577.
DR PDB; 2LUE; NMR; -; B=169-185.
DR PDB; 3VTV; X-ray; 1.70 A; A=175-181.
DR PDB; 3VTW; X-ray; 2.52 A; A/B/C=175-181.
DR PDBsum; 2LO4; -.
DR PDBsum; 2LUE; -.
DR PDBsum; 3VTV; -.
DR PDBsum; 3VTW; -.
DR ProteinModelPortal; Q96CV9; -.
DR SMR; Q96CV9; 550-577.
DR DIP; DIP-42001N; -.
DR IntAct; Q96CV9; 60.
DR MINT; MINT-155870; -.
DR PhosphoSite; Q96CV9; -.
DR DMDM; 62287118; -.
DR PaxDb; Q96CV9; -.
DR PRIDE; Q96CV9; -.
DR DNASU; 10133; -.
DR Ensembl; ENST00000263036; ENSP00000263036; ENSG00000123240.
DR Ensembl; ENST00000378747; ENSP00000368021; ENSG00000123240.
DR Ensembl; ENST00000378748; ENSP00000368022; ENSG00000123240.
DR Ensembl; ENST00000378752; ENSP00000368027; ENSG00000123240.
DR Ensembl; ENST00000378757; ENSP00000368032; ENSG00000123240.
DR Ensembl; ENST00000378764; ENSP00000368040; ENSG00000123240.
DR GeneID; 10133; -.
DR KEGG; hsa:10133; -.
DR UCSC; uc001ilu.1; human.
DR CTD; 10133; -.
DR GeneCards; GC10P013055; -.
DR HGNC; HGNC:17142; OPTN.
DR HPA; CAB019303; -.
DR HPA; HPA003279; -.
DR HPA; HPA003360; -.
DR MIM; 137760; phenotype.
DR MIM; 602432; gene.
DR MIM; 606657; phenotype.
DR MIM; 613435; phenotype.
DR neXtProt; NX_Q96CV9; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 353225; Primary adult open-angle glaucoma.
DR PharmGKB; PA31948; -.
DR eggNOG; NOG138369; -.
DR HOVERGEN; HBG106481; -.
DR InParanoid; Q96CV9; -.
DR OMA; LAHPNLD; -.
DR OrthoDB; EOG7D2FD7; -.
DR PhylomeDB; Q96CV9; -.
DR Reactome; REACT_115566; Cell Cycle.
DR ChiTaRS; OPTN; human.
DR GeneWiki; Optineurin; -.
DR GenomeRNAi; 10133; -.
DR NextBio; 38327; -.
DR PRO; PR:Q96CV9; -.
DR Bgee; Q96CV9; -.
DR Genevestigator; Q96CV9; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0008219; P:cell death; TAS:ProtInc.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; TAS:Reactome.
DR GO; GO:0090161; P:Golgi ribbon formation; IDA:UniProtKB.
DR GO; GO:0043001; P:Golgi to plasma membrane protein transport; IMP:UniProtKB.
DR GO; GO:0000042; P:protein targeting to Golgi; IMP:UniProtKB.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR InterPro; IPR021063; NEMO_N.
DR Pfam; PF11577; NEMO; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amyotrophic lateral sclerosis;
KW Coiled coil; Complete proteome; Cytoplasm; Disease mutation; Glaucoma;
KW Golgi apparatus; Neurodegeneration; Phosphoprotein; Polymorphism;
KW Reference proteome.
FT CHAIN 1 577 Optineurin.
FT /FTId=PRO_0000058066.
FT REGION 58 209 Interaction with Rab8.
FT REGION 411 577 Interaction with HD.
FT REGION 412 520 Interaction with MYO6.
FT COILED 38 170 Potential.
FT COILED 239 508 Potential.
FT MOTIF 474 479 UBAN.
FT MOD_RES 177 177 Phosphoserine; by TBK1.
FT VAR_SEQ 1 57 Missing (in isoform 3).
FT /FTId=VSP_013261.
FT VAR_SEQ 210 215 Missing (in isoform 2).
FT /FTId=VSP_013262.
FT VARIANT 26 26 H -> D (in GLC1E).
FT /FTId=VAR_021537.
FT VARIANT 50 50 E -> K (in GLC1E; dbSNP:rs28939688).
FT /FTId=VAR_021538.
FT VARIANT 98 98 M -> K (may modify intraocular pressure
FT and increase risk of GLC1E and NPG; may
FT be a common polymorphism;
FT dbSNP:rs11258194).
FT /FTId=VAR_021539.
FT VARIANT 103 103 E -> D (in GLC1E).
FT /FTId=VAR_021540.
FT VARIANT 201 201 P -> S.
FT /FTId=VAR_021541.
FT VARIANT 213 213 K -> H (requires 2 nucleotide
FT substitutions).
FT /FTId=VAR_021542.
FT VARIANT 216 216 S -> R.
FT /FTId=VAR_021543.
FT VARIANT 308 308 S -> P (in dbSNP:rs7068431).
FT /FTId=VAR_030769.
FT VARIANT 322 322 K -> E (in dbSNP:rs523747).
FT /FTId=VAR_021544.
FT VARIANT 357 357 T -> P.
FT /FTId=VAR_021545.
FT VARIANT 478 478 E -> G (in ALS12).
FT /FTId=VAR_063597.
FT VARIANT 486 486 H -> R (in GLC1E; juvenile onset).
FT /FTId=VAR_021546.
FT VARIANT 545 545 R -> Q (in GLC1E; unknown pathological
FT significance; dbSNP:rs28939689).
FT /FTId=VAR_021547.
FT MUTAGEN 474 474 D->N: Significant reduction in ubiquitin
FT binding and interaction with TBK1. Loss
FT of ability to inhibit the activation of
FT the IFNB promoter in response to TLR3 or
FT RIG-I signaling.
FT CONFLICT 436 436 A -> V (in Ref. 8; AAC26850).
FT STRAND 178 180
FT TURN 556 560
FT HELIX 566 574
SQ SEQUENCE 577 AA; 65921 MW; DB0F841E3315AAE1 CRC64;
MSHQPLSCLT EKEDSPSEST GNGPPHLAHP NLDTFTPEEL LQQMKELLTE NHQLKEAMKL
NNQAMKGRFE ELSAWTEKQK EERQFFEIQS KEAKERLMAL SHENEKLKEE LGKLKGKSER
SSEDPTDDSR LPRAEAEQEK DQLRTQVVRL QAEKADLLGI VSELQLKLNS SGSSEDSFVE
IRMAEGEAEG SVKEIKHSPG PTRTVSTGTA LSKYRSRSAD GAKNYFEHEE LTVSQLLLCL
REGNQKVERL EVALKEAKER VSDFEKKTSN RSEIETQTEG STEKENDEEK GPETVGSEVE
ALNLQVTSLF KELQEAHTKL SKAELMKKRL QEKCQALERK NSAIPSELNE KQELVYTNKK
LELQVESMLS EIKMEQAKTE DEKSKLTVLQ MTHNKLLQEH NNALKTIEEL TRKESEKVDR
AVLKELSEKL ELAEKALASK QLQMDEMKQT IAKQEEDLET MTILRAQMEV YCSDFHAERA
AREKIHEEKE QLALQLAVLL KENDAFEDGG RQSLMEMQSR HGARTSDSDQ QAYLVQRGAE
DRDWRQQRNI PIHSCPKCGE VLPDIDTLQI HVMDCII
//

MIM 137760
*RECORD*
*FIELD* NO
137760
*FIELD* TI
#137760 GLAUCOMA, PRIMARY OPEN ANGLE; POAG
GLAUCOMA 1, OPEN ANGLE, E, INCLUDED; GLC1E, INCLUDED;;
read moreGLAUCOMA, PRIMARY OPEN ANGLE, ADULT-ONSET, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because this form of
adult-onset primary open angle glaucoma (POAG), designated GLC1E, is
caused by mutation in the OPTN gene (602432) on chromosome 10p.

DESCRIPTION

Quigley (1993) reviewed adult-onset primary open angle glaucoma, which
combines a particular abnormal appearance of the optic disc (optic nerve
head) with a slowly progressive loss of visual sensitivity. Many
patients with glaucoma have intraocular pressures above the normal
range, although this cannot be considered part of the definition of the
disease, since some patients have normal intraocular pressures. Changes
in the optic disc, either inherited or acquired, contribute to the
development of the disorder, which leads to visual loss from increasing
nerve fiber layer atrophy. Quigley et al. (1994) stated that POAG should
be reviewed as a multifactorial disorder.

- Genetic Heterogeneity of Primary Open Angle Glaucoma

Other forms of primary open angle glaucoma include GLC1A (137750),
caused by mutation in the MYOC gene (601652) on chromosome 1q24.3-q25.2;
GLC1B (606689) on chromosome 2cen-q13; GLC1C (601682) on chromosome
3q21-q24; GLC1D (602429) on chromosome 8q23; GLC1F (603383), caused by
mutation in the ASB10 gene on chromosome 7q36; GLC1G (609887), caused by
mutation in the WDR36 gene (609669) on chromosome 5q22; GLC1H (611276)
on chromosome 2p16-p15; GLC1I (609745) on chromosome 15q11-q13; GLC1J
(608695) on chromosome 9q22; GLC1K (608696) on chromosome 20p12; GLC1L
(see 137750) on chromosome 3p22-p21; GLC1M (610535) on chromosome 5q22;
GLC1N (611274) on chromosome 15q22-q24; GLC1O (613100), caused by
mutation in the NTF4 gene (162662) on chromosome 19q13.3; GLC1P
(177700), caused by an approximately 300-kb duplication on chromosome
12q24, most likely involving the TBK1 gene (604834).

Nail-patella syndrome (NPS; 161200), which is caused by mutation in the
LMX1B gene (602575) on chromosome 9q34, has open angle glaucoma as a
pleiotropic feature.

- Other Forms of Glaucoma

For a general description and a discussion of genetic heterogeneity of
congenital forms of glaucoma, see GLC3A (231300).

See 606657 for a discussion of normal tension glaucoma (NTG) or normal
pressure glaucoma (NPG), a subtype of POAG.

CLINICAL FEATURES

Tanito et al. (2004) described the use of a digitized laser slit lamp
that uses a helium-neon laser as a light source in detecting reduction
of posterior pole retinal thickness in glaucoma. Posterior pole retinal
thickness was found to be decreased in early and moderate stage POAG.
Reduction of perifoveal retinal thickness was correlated with visual
field loss.

In a study of 4,319 subjects in the Beijing Eye Study stratified into
several myopia subgroups, Xu et al. (2007) found that marked to high
myopia with a myopic refractive error exceeding -6 diopters was
associated with a high prevalence of glaucomatous optic neuropathy.

BIOCHEMICAL FEATURES

Using topical application of dexamethasone, Armaly (1966) concluded that
subjects can be divided into 3 classes according to the response of
intraocular pressure--high, intermediate, and low. He interpreted these
3 phenotypes to correspond to the 3 genotypes of a 2-allele system.

Southren et al. (1985) presented evidence for an alteration in cortisol
metabolism in primary open angle glaucoma. Changes in 2 enzymes were
found: a greater than 100-fold increase in cortisol delta-4-reductase
and a 4-fold or greater decrease in 3-oxidoreductase activities. The
increase of the former activity appeared to be the result of increased
synthesis of the enzyme. In normal mammalian tissues, cortisol is
metabolized by delta-4-reductase to dihydrocortisol and then by
3-oxidoreductase to tetrahydrocortisol with no significant accumulation
of dihydrocortisol. The intermediate 5-beta-dihydrocortisol that
accumulates in human trabecular meshwork (TM) at the angle of the
anterior chamber in cases of POAG potentiates effects of glucocorticoids
in raising intraocular pressure in rabbits.

Yang et al. (2001) analyzed T-cell subsets and levels of cytokine IL2
(147680) and soluble IL2 receptor (see, e.g., 147730) in the peripheral
blood of patients with normal pressure glaucoma and primary open angle
glaucoma and compared them to values in age-matched controls. They found
increased frequency of CD8+/HLA-DR+ lymphocytes in patients with NPG and
increased CD3+/CD8+ lymphocytes in both NPG and POAG patients. CD5+
lymphocytes were higher only in POAG patients. The mean concentration of
soluble IL2R was higher in NPG and POAG patients than in controls
although the IL2 concentration was similar in patients and controls.
Also, the reactivity of T lymphocytes to the nonspecific reagent
phytohemagglutinin was reduced significantly in both NPG and POAG
patients. The authors concluded that the immune system might play an
important role in initiation or progression of glaucomatous optic
neuropathy in some patients.

Although POAG has traditionally been associated with high IOP, glaucoma
is considered a multifactorial disorder. Ferreira et al. (2004) measured
the total reactive antioxidant potential (TRAP) and the activities of
antioxidant enzymes in the aqueous humor of 24 POAG patients and 24
controls. The authors found that superoxide dismutase (SOD; 147450)
activity, glutathione peroxidase (GPX; 138320) activity, and TRAP might
be useful oxidative stress markers in the aqueous humor of glaucoma
patients.

Gherghel et al. (2005) found that patients with newly diagnosed POAG
exhibited low levels of circulating glutathione, suggesting a general
compromise of the antioxidative defense system.

Transforming growth factor beta-2 (TGFB2; 190220) is present at elevated
levels in the aqueous humor of patients with POAG. Studies have shown
that TGFB2 influences cultured trabecular meshwork cells. Gottanka et
al. (2004) found that TGFB2 reduced outflow facility when perfused into
cultured human anterior segments. Furthermore, TGFB2 affected the
extracellular matrix of the trabecular meshwork in a manner that was
consistent with the observed reduction in outflow facility. Although the
distribution of accumulated fibrillar material was different in these
perfused eyes than that in POAG, the difference could have been due to
variation in biomechanical environment for trabecular meshwork cells in
cultured anterior segments compared with the living eye. Overall, the
results supported the hypothesis that elevated TGFB2 levels in the
aqueous humor played a role in the pathogenesis of the ocular
hypertension in POAG.

Xue et al. (2007) found that human trabecular meshworks from glaucoma
donors exhibited significantly higher activity levels of the
calcification marker alkaline phosphatase (ALP) than their matched
counterparts with normal eyes. Dexamethasone (Dex) and TGFB2, both of
which are associated with glaucoma, significantly induced the
upregulation of ALP activity in 2 trabecular meshwork primary cell
lines. Silencing the inhibitor of calcification matrix Gla (MGP; 154870)
by siRNA resulted in ALP activity that was increased by 197%. Xue et al.
(2007) concluded that the increased activity of the calcification marker
ALP in glaucomatous trabecular meshworks might be indicative of an
underlying mineralization process during development of the disease.
Inhibition of the calcification mechanism represented by the presence of
active MGP appeared to be compromised in glaucomatous tissue.

Wordinger et al. (2007) studied the effects of altered bone
morphogenetic protein signaling on intraocular pressure in POAG. They
found that human trabecular meshwork synthesized and secreted BMP4
(112262) as well as expressed the BMP receptor subtypes BMPR1 (see
601299) and BMPR2 (600799). TM cells responded to exogenous BMP4 by
phosphorylating SMAD signaling proteins (see 601595). Cultured human TM
cells treated with TGFB2 significantly increased fibronectin (FN;
135600) levels, and BMP4 blocked this FN induction. There was
significant elevation of mRNA and protein levels of the BMP antagonist
Gremlin (GREM1; 603054) in glaucomatous TM cells. In addition, Gremlin
was present in human aqueous humor. Gremlin blocked the negative effect
of BMP4 on TGFB2 induction of FN. Addition of recombinant Gremlin to the
medium of ex vivo perfusion-cultured human eye anterior segments caused
the glaucoma phenotype of elevated IOP. Wordinger et al. (2007)
concluded that these results were consistent with the hypothesis that,
in POAG, elevated expression of Gremlin by TM cells inhibited BMP4
antagonism of TGFB2 and led to increased extracellular matrix deposition
and elevated IOP.

Wang et al. (2006) assessed endothelin B receptor (EDNRB; 131244)
expression in human glaucomatous optic nerves and the spatial
relationship between EDNRB and astrocytes. The frequency of positive
EDNRB immunoreactivity was significantly higher in human glaucomatous
optic nerves as compared with age-matched controls (9/16 vs 1/10). EDNRB
colocalized with astrocytic processes and was quantitatively higher in
the glaucomatous eyes. Wang et al. (2006) concluded that increased EDNRB
immunoreactivity in diseased optic nerves and its association with
astrocytes suggested that the glia-endothelin system might be involved
in the pathologic mechanisms of neuronal degeneration.

Polak et al. (2007) investigated the ocular blood flow response to
systemic nitric oxide synthase (NOS; see 163731) inhibition in 12
patients with POAG and age-matched controls. POAG patients showed an
abnormal blood flow response in the optic nerve head and the choroid as
compared with controls, despite a comparable increase in systemic blood
pressure. Polak et al. (2007) suggested that the NO system may be an
attractive target for therapeutic interventions in glaucoma.

Bahler et al. (2008) studied the effects of 2 prostaglandin analogs,
latanaprost free acid and prostaglandin E1 (PGE1), on outflow facility
in cultured human anterior segments. They studied cultured anterior
segments to eliminate the uveoscleral pathway and enable a direct
assessment of trabecular outflow. Histologic changes indicated that
prostaglandins have a direct trabecular meshwork effect.

INHERITANCE

Studies in families with and without cases of glaucoma led Armaly et al.
(1968) to the conclusion that intraocular pressure and outflow facility
are multifactorial in determination and that open angle glaucoma is
probably multifactorial also. Schwartz et al. (1972) found low
concordance in a twin study of effect of corticosteroids on intraocular
pressure and concluded that inheritance is multifactorial.

The adult-onset primary open angle glaucoma usually has its onset after
the age of 50 and is probably inherited as a complex trait, without an
obvious segregation pattern.

Klein et al. (2004) investigated the family aggregation and heritability
of risk indicators of primary open angle glaucoma. Heritability
estimates were 0.36 for intraocular pressure, 0.55 for optic cup
diameter, 0.57 for optic disc diameter, and 0.48 for cup-to-disc ratio.
Correlations for the optic disc parameters were compatible with the
amount of gene sharing in relative pairs of different degrees. The
authors concluded that risk indicators for open angle glaucoma
correlated highly in families, and the patterns were consistent with the
hypothesis of genetic determinants of these factors.

Hewitt et al. (2007) performed a 2-stage study in a population-based
sample of twins to determine the principal heritable components of
visible optic nerve head structures that might be involved in the
etiology of common blinding diseases such as glaucoma. Their results
suggested that the shape and size of the optic disc and cup are more
heritable and should receive a greater priority for quantification than
should vascular features.

POPULATION GENETICS

Coulehan et al. (1980) found that black participants in a glaucoma
screening program had higher mean intraocular pressures, more frequent
pathologic disc changes, and more new cases of glaucoma discovered than
did whites matched for sex and age. In a 3-year period, blacks accounted
for 23% of hospitalizations for chronic open angle glaucoma in 10
Pennsylvania counties, rather than the expected 6.3%. Among those
hospitalized for open angle glaucoma, blacks were younger than whites.

MAPPING

Sarfarazi et al. (1998) identified a locus, designated GLC1E, in the
10p15-p14 region in a large British family with a classic form of normal
tension glaucoma (606657). Of the 42 meioses genotyped in this pedigree,
39 subjects (16 affected) inherited a haplotype compatible with their
prior clinical designation, whereas the remaining 3 were classified as
unknown. Although a maximum lod score of 10 at a recombination fraction
of 0.00 was obtained with D10S1216, 21 other markers provided
significant values varying between 3.77 and 9.70. When only the affected
meioses of this kindred were analyzed, lod scores remained statistically
significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Mutations in
the OPTN gene were found to be a cause of POAG linked to chromosome 10p
(Rezaie et al., 2002).

Nemesure et al. (2003) noted that 6 named loci contributing to POAG
susceptibility had been identified by genetic linkage studies performed
predominantly in Caucasian families. They evaluated the genetic
component of POAG in a population of African descent in Barbados, West
Indies, and found evidence of POAG loci located on chromosomes 2q and
10p.

- Mapping by Genome Scan

Wiggs et al. (2000) performed a 2-stage genome scan using an initial
pedigree set of 113 affected sib pairs and a second pedigree set of 69
affected sib pairs. In the combined data analysis, 5 regions (2, 14,
17p, 17q, and 19) produced a multipoint lod score greater than 2.0
between microsatellite markers and POAG. Multipoint analysis using ASPEX
also showed significant results on chromosomes 2, 14, 17p, 17q, and 19.

- Associations Pending Confirmation

Burdon et al. (2011) performed a genomewide association study in 590
patients with advanced POAG, with replication in an additional 334
patients with advanced OAG, 465 patients with less-severe POAG, and 93
cases from another glaucoma cohort. They found association with a SNP
(dbSNP rs4656461) located approximately 6.5 kb downstream of the TMCO1
gene (614123) on chromosome 1q24.1 (combined p = 6.00 x 10(-14); odds
ratio, 1.51), and with a SNP (dbSNP rs4977756) in the CDKN2BAS gene
(613149) on chromosome 9p21 (combined p = 1.35 x 10(-14); odds ratio,
1.39). Burdon et al. (2011) also demonstrated retinal expression of
genes at both loci in human ocular tissue.

- Exclusion Studies

In 18 families with POAG in the United States, Allingham et al. (1998)
excluded 2cen-q13 as the site of the mutation causing POAG.

DIAGNOSIS

Open angle glaucoma accounts for approximately 3% of blindness in white
and 7.9% in black American populations (Quigley and Vitale, 1997). The
disorder is diagnosed clinically by 3 tests to reveal characteristic
glaucomatous optic nerve damage, characteristic visual field loss, and
increased intraocular pressures (IOP). Normal or low tension glaucoma
(606657) is a form of open angle glaucoma in which the typical
glaucomatous cupping of the optic nerve head and visual field loss are
present, but in which the recorded IOPs are consistently within the
statistically normal range of less than 22 mm Hg. This form may account
for about one-fifth of primary open angle glaucoma, although a single
screening test may record normal tension glaucoma in more than one-half
of cases.

MOLECULAR GENETICS

Rezaie et al. (2002) identified mutations in the OPTN gene (602432) in
patients with adult-onset POAG. They found that mutations in OPTN
account for 17% of patients with hereditary POAG, including individuals
with normal intraocular pressure.

Chalasani et al. (2007) explored functional features of optineurin and
its mutants. The E50K mutation (602432.0001) acquired the ability to
induce cell death selectively in retinal ganglion cells. This cell death
was mediated by oxidative stress. Chalasani et al. (2007) concluded that
these findings raised the possibility of antioxidant use for delaying or
controlling some forms of glaucoma.

- Exclusion Studies

Nemesure et al. (2003) did not find support for myocilin (MYOC; 601652)
or optineurin as a causative gene in an Afro-Caribbean population known
to have relatively high rates of POAG.

Leung et al. (2000) found no abnormality of the TISR/oculomedin coding
sequence or proximal promoter mutation in 110 Chinese patients with
primary open angle glaucoma.

ANIMAL MODEL

Open angle glaucoma is characterized by loss of retinal ganglion cells
(RGCs), cupping of the optic disc, and defects in the visual field.
Increased intraocular pressure (IOP) is the major known risk factor that
produces glaucoma and glaucoma-like damage to the optic nerve and RGCs
in experimental primate models. Harwerth et al. (1999) used argon laser
treatments to the trabecular meshwork in 1 eye of each of 10 rhesus
monkeys to create successful experimental glaucoma. Elevated intraocular
pressure, followed by ganglion cell loss and visual field defects,
ensued. However, other factors may interact with IOP to modulate its
effect on the optic nerve. Disturbances of blood flow in the optic nerve
head may be such a factor. Chauhan et al. (2004) described a model of
chronic endothelin-1 (ET1; 131240) administration to the rat optic nerve
and evaluated its effect on RGC and axon survival. ET1 led to a mean
reduction in optic nerve blood flow of 68%. This resulted in a
time-dependent loss of RGCs and their axons without apparent change in
the optic disc topography.

Johnson et al. (2007) studied global gene expression changes in the
optic nerve head (ONH) in a rat model of glaucoma with unilateral
sustained IOP elevation. Microarray analysis identified more than 2,000
significantly regulated genes. For 225 of these genes, the changes were
greater than 2-fold. The most significantly affected gene classes were
cell proliferation, immune response, lysosome, cytoskeleton,
extracellular matrix, and ribosome. A 2.7-fold increase in ONH
cellularity confirmed glaucoma model cell proliferation. By quantitative
PCR, increases in levels of periostin (608777), collagen VI (see
120220), and TGFB1 (190180) were linearly correlated to the degree of
IOP-induced injury. For cyclin D1 (168461), fibulin-2 (135820), tenascin
C (187380), TIMP1 (305370), and aquaporin-4 (600308), correlations were
significantly nonlinear, displaying maximum changes with focal injury.

HISTORY

Sarfarazi (1997) reviewed advances concerning the molecular genetics of
glaucomas. At the time of their review, 2 loci, GLC3A (231300) and GLC3B
(600975), had been identified for primary congenital glaucoma, and
mutations had been identified in the cytochrome p450 CYP1B1 gene
(601771) in the former. The GLC1A locus had been identified for
juvenile-onset primary open angle glaucoma, and mutations in MYOC
(601652) identified. Furthermore, 2 loci, GLC1B (606689) and GLC1C
(601682), had been identified for late-onset chronic open angle glaucoma
by linkage studies.

*FIELD* SA
Harris (1965); Raymond (1997); Schwartz (1978); Wiggs et al. (1996);
Wiggs et al. (2004)
*FIELD* RF
1. Allingham, R. R.; Wiggs, J. L.; Damji, K. F.; Herndon, L.; Youn,
J.; Tallett, D. A.; Jones, K. H.; Del Bono, E. A.; Reardon, M.; Haines,
J. L.; Pericak-Vance, M. A.: Adult-onset primary open angle glaucoma
does not localize to chromosome 2cen-q13 in North American families. Hum.
Hered. 48: 251-255, 1998.

2. Armaly, M. F.: The heritable nature of dexamethasone induced ocular
hypertension. Arch. Ophthal. 75: 32-35, 1966.

3. Armaly, M. F.; Monstavicius, B. F.; Sayegh, R. E.: Ocular pressure
and aqueous outflow facility in siblings. Arch. Ophthal. 80: 354-360,
1968.

4. Bahler, C. K.; Howell, K. G.; Hann, C. R.; Fautsch, M. P.; Johnson,
D. H.: Prostaglandins increase trabecular meshwork outflow facility
in cultured human anterior segments. Am. J. Ophthal. 145: 114-119,
2008.

5. Burdon, K. P.; Macgregor, S.; Hewitt, A. W.; Sharma, S.; Chidlow,
G.; Mills, R. A.; Danoy, P.; Casson, R.; Viswanathan, A. C.; Liu,
J. Z.; Landers, J.; Henders, A. K.; and 13 others: Genome-wide
association study identifies susceptibility loci for open angle glaucoma
at TMCO1 and CDKN2B-AS1. Nature Genet. 43: 574-578, 2011.

6. Chalasani, M. L.; Radha, V.; Gupta, V.; Agarwal, N.; Balasubramanian,
D.; Swarup, G.: A glaucoma-associated mutant of optineurin selectively
induces death of retinal ganglion cells which is inhibited by antioxidants. Invest.
Ophthal. Vis. Sci. 48: 1607-1614, 2007.

7. Chauhan, B. C.; LeVatte, T. L.; Jollimore, C. A.; Yu, P. K.; Reitsamer,
H. A.; Kelly, M. E. M.; Yu, D.-Y.; Tremblay, F.; Archibald, M. L.
: Model of endothelin-1-induced chronic optic neuropathy in rat. Invest.
Ophthal. Vis. Sci 45: 144-150, 2004.

8. Coulehan, J. L.; Helzlsouer, K. J.; Rogers, K. D.; Brown, S. I.
: Racial differences in intraocular tension and glaucoma surgery. Am.
J. Epidemiol. 111: 759-768, 1980.

9. Ferreira, S. M.; Lerner, S. F.; Brunzini, R.; Evelson, P. A.; Llesuy,
S. F.: Oxidative stress markers in aqueous humor of glaucoma patients. Am.
J. Ophthal. 137: 62-69, 2004.

10. Gherghel, D.; Griffiths, H. R.; Hilton, E. J.; Cunliffe, I. A.;
Hosking, S. L.: Systemic reduction in glutathione levels occurs in
patients with primary open-angle glaucoma. Invest. Ophthal. Vis.
Sci. 46: 877-883, 2005.

11. Gottanka, J.; Chan, D.; Eichhorn, M.; Lutjen-Drecoll, E.; Ethier,
C. R.: Effects of TGF-beta-2 in perfused human eyes. Invest. Ophthal.
Vis. Sci. 45: 153-158, 2004.

12. Harris, D.: The inheritance of glaucoma. Am. J. Ophthal. 60:
91-95, 1965.

13. Harwerth, R. S.; Carter-Dawson, L.; Shen, F.; Smith, E. L., III;
Crawford, M. L. J.: Ganglion cell losses underlying visual field
defects from experimental glaucoma. Invest. Ophthal. Vis. Sci. 40:
2242-2250, 1999.

14. Hewitt, A. W.; Poulsen, J. P.; Alward, W. L. M.; Bennett, S. L.;
Budde, W. M.; Cooper, R. L.; Craig, J. E.; Fingert, J. H.; Foster,
P. J.; Garway-Heath, D. F.; Green, C. M.; Hammond, C. J.; and 11
others: Heritable features of the optic disc: a novel twin method
for determining genetic significance. Invest. Ophthal. Vis. Sci. 48:
2469-2475, 2007.

15. Johnson, E. C.; Jia, L.; Cepurna, W. O.; Doser, T. A.; Morrison,
J. C.: Global changes in optic nerve head gene expression after exposure
to elevated intraocular pressure in a rat glaucoma model. Invest.
Ophthal. Vis. Sci. 48: 3161-3177, 2007.

16. Klein, B. E. K.; Klein, R.; Lee, K. E.: Heritability of risk
factors for primary open-angle glaucoma: the Beaver Dam eye study. Invest.
Ophthal. Vis. Sci. 45: 59-62, 2004.

17. Leung, Y. F.; Baum, L.; Lam, D. S. C.; Fan, D. S. P.; Chua, J.
K. H.; Pang, C. P.: Absence of trabecular meshwork-inducible stretch
response (TISR)/oculomedin gene and proximal promoter mutation in
primary open angle glaucoma patients. Hum. Genet. 107: 404-405,
2000.

18. Nemesure, B.; Jiao, X.; He, Q.; Leske, M. C.; Wu, S.-Y.; Hennis,
A.; Mendell, N.; Redman, J.; Garchon, H.-J.; Agarwala, R.; Schaffer,
A. A.; Hejtmancik, F.; Barbados Family Study Group: A genome-wide
scan for primary open-angle glaucoma (POAG): the Barbados family study
of open-angle glaucoma. Hum. Genet. 112: 600-609, 2003.

19. Polak, K.; Luksch, A.; Berisha, F.; Fuchsjaeger-Mayrl, G.; Dallinger,
S.; Schmetterer, L.: Altered nitric oxide system in patients with
open-angle glaucoma. Arch. Ophthal. 125: 494-498, 2007.

20. Quigley, H. A.: Open-angle glaucoma. New Eng. J. Med. 328:
1097-1106, 1993.

21. Quigley, H. A.; Enger, C.; Katz, J.; Sommer, A.; Scott, R.; Gilbert,
D.: Risk factors for the development of glaucomatous visual field
loss in ocular hypertension. Arch. Ophthal. 112: 644-649, 1994.

22. Quigley, H. A.; Vitale, S.: Models of open-angle glaucoma prevalence
and incidence in the United States. Invest. Ophthal. Vis. Sci. 38:
83-91, 1997.

23. Raymond, V.: Molecular genetics of the glaucomas: mapping of
the first five 'GLC' loci. (Editorial) Am. J. Hum. Genet. 60: 272-277,
1997.

24. Rezaie, T.; Child, A.; Hitchings, R.; Brice, G.; Miller, L.; Coca-Prados,
M.; Heon, E.; Krupin, T.; Ritch, R.; Kreutzer, D.; Crick, R. P.; Sarfarazi,
M.: Adult-onset primary open-angle glaucoma caused by mutations in
optineurin. Science 295: 1077-1079, 2002.

25. Sarfarazi, M.: Recent advances in molecular genetics of glaucomas. Hum.
Molec. Genet. 6: 1667-1677, 1997.

26. Sarfarazi, M.; Child, A.; Stoilova, D.; Brice, G.; Desai, T.;
Trifan, O. C.; Poinoosawmy, D.; Crick, R. P.: Localization of the
fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to
the 10p15-p14 region. Am. J. Hum. Genet. 62: 641-652, 1998.

27. Schwartz, B.: Current concepts in ophthalmology: the glaucomas. New
Eng. J. Med. 299: 182-184, 1978.

28. Schwartz, J. T.; Reuling, F. H.; Feinleib, M.; Garrison, R. J.;
Collie, D. J.: Twin heritability study of the effect of corticosteroids
on intraocular pressure. J. Med. Genet. 9: 137-143, 1972.

29. Southren, A. L.; Gordon, G. G.; Weinstein, B. I.: Genetic defect
in cortisol metabolism in primary open angle glaucoma. Trans. Assoc.
Am. Phys. 98: 361-369, 1985.

30. Tanito, M.; Itai, N.; Ohira, A.; Chihara, E.: Reduction of posterior
pole retinal thickness in glaucoma detected using the retinal thickness
analyzer. Ophthalmology 111: 265-275, 2004.

31. Wang, L.; Fortune, B.; Cull, G.; Dong, J.; Cioffi, G. A.: Endothelin
B receptor in human glaucoma and experimentally induced optic nerve
damage. Arch. Ophthal. 124: 717-724, 2006.

32. Wiggs, J. L.; Allingham, R. R.; Hossain, A.; Kern, J.; Auguste,
J.; DelBono, E. A.; Broomer, B.; Graham, F. L.; Hauser, M.; Pericak-Vance,
M.; Haines, J. L.: Genome-wide scan for adult onset primary open
angle glaucoma. Hum. Molec. Genet. 9: 1109-1117, 2000.

33. Wiggs, J. L.; Damji, K. F.; Haines, J. L.; Pericak-Vance, M. A.;
Allingham, R. R.: The distinction between juvenile and adult-onset
primary open-angle glaucoma. (Letter) Am. J. Hum. Genet. 58: 243-244,
1996.

34. Wiggs, J. L.; Lynch, S.; Ynagi, G.; Maselli, M.; Auguste, J.;
Del Bono, E. A.; Olson, L. M.; Haines, J. L.: A genomewide scan identifies
novel early-onset primary open-angle glaucoma loci on 9q22 and 20p12. Am.
J. Hum. Genet. 74: 1314-1320, 2004.

35. Wordinger, R. J.; Fleenor, D. L.; Hellberg, P. E.; Pang, I.-H.;
Tovar, T. O.; Zode, G. S.; Fuller, J. A.; Clark, A. F.: Effects of
TGF-beta-2, BMP-4, and gremlin in the trabecular meshwork: implications
for glaucoma. Invest. Ophthal. Vis. Sci. 48: 1191-1200, 2007.

36. Xu, L.; Wang, Y.; Wang, S.; Wang, Y.; Jonas, J. B.: High myopia
and glaucoma susceptibility: the Beijing Eye Study. Ophthalmology 114:
216-220, 2007.

37. Xue, W.; Comes, N.; Borras, T.: Presence of an established calcification
marker in trabecular meshwork tissue of glaucoma donors. Invest.
Ophthal. Vis. Sci. 48: 3184-3194, 2007.

38. Yang, J.; Patil, R. V.; Yu, H.; Gordon, M.; Wax, M. B.: T cell
subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am. J.
Ophthal. 131: 421-426, 2001.

*FIELD* CS
Eyes:
Open angle glaucoma;
Myopia

Misc:
More frequent among African Americans

Inheritance:
Autosomal dominant

*FIELD* ED
joanna: 01/28/1999

*FIELD* CN
Marla J. F. O'Neill - updated: 6/11/2013
Marla J. F. O'Neill - updated: 3/28/2013
Marla J. F. O'Neill - updated: 3/27/2013
Marla J. F. O'Neill - updated: 12/6/2011
Marla J. F. O'Neill - updated: 6/21/2011
Marla J. F. O'Neill - updated: 10/22/2009
Jane Kelly - updated: 7/2/2008
Jane Kelly - updated: 4/17/2008
Jane Kelly - updated: 12/7/2007
Jane Kelly - updated: 11/28/2007
Jane Kelly - updated: 10/30/2007
Jane Kelly - updated: 10/18/2007
Jane Kelly - updated: 9/25/2007
Jane Kelly - updated: 12/7/2006
Jane Kelly - updated: 7/7/2005
Jane Kelly - updated: 7/30/2004
Jane Kelly - updated: 6/14/2004
Jane Kelly - updated: 3/11/2004
Victor A. McKusick - updated: 5/8/2003
Victor A. McKusick - updated: 8/12/2002
Ada Hamosh - updated: 2/13/2002
Jane Kelly - updated: 2/12/2002
Victor A. McKusick - updated: 12/5/2000
George E. Tiller - updated: 5/12/2000
Victor A. McKusick - updated: 1/20/1999
Victor A. McKusick - updated: 3/9/1998
Moyra Smith - edited: 8/30/1996

*FIELD* CD
Victor A. McKusick: 10/16/1986

*FIELD* ED
carol: 06/12/2013
carol: 6/11/2013
carol: 3/28/2013
terry: 3/27/2013
joanna: 3/18/2013
alopez: 12/7/2011
terry: 12/6/2011
carol: 6/22/2011
carol: 6/21/2011
wwang: 5/6/2010
carol: 2/23/2010
wwang: 1/8/2010
wwang: 10/22/2009
terry: 10/22/2009
terry: 9/25/2008
carol: 7/2/2008
carol: 4/17/2008
carol: 12/7/2007
carol: 11/28/2007
carol: 11/20/2007
carol: 10/30/2007
carol: 10/18/2007
carol: 9/25/2007
carol: 8/1/2007
carol: 12/7/2006
terry: 12/7/2006
carol: 10/30/2006
carol: 10/25/2006
alopez: 2/14/2006
alopez: 11/28/2005
joanna: 8/29/2005
carol: 8/2/2005
alopez: 7/7/2005
terry: 3/11/2005
ckniffin: 10/27/2004
tkritzer: 8/4/2004
terry: 7/30/2004
alopez: 6/14/2004
alopez: 3/15/2004
terry: 3/11/2004
tkritzer: 5/13/2003
tkritzer: 5/9/2003
terry: 5/8/2003
cwells: 8/12/2002
carol: 2/15/2002
carol: 2/14/2002
carol: 2/13/2002
terry: 2/13/2002
carol: 2/12/2002
mcapotos: 12/5/2000
alopez: 5/12/2000
carol: 1/28/1999
terry: 1/20/1999
alopez: 3/10/1998
alopez: 3/9/1998
terry: 3/3/1998
mark: 9/13/1996
mark: 9/12/1996
terry: 9/4/1996
mark: 8/30/1996
mark: 1/25/1996
terry: 1/23/1996
mark: 11/14/1995
carol: 1/3/1995
mimadm: 9/24/1994
pfoster: 7/20/1994
carol: 5/14/1993
supermim: 3/16/1992

MIM 602432
*RECORD*
*FIELD* NO
602432
*FIELD* TI
*602432 OPTINEURIN; OPTN
;;14.7K-INTERACTING PROTEIN; FIP2;;
HYPL;;
TRANSCRIPTION FACTOR IIIA-INTERACTING PROTEIN;;
read moreTFIIIA-INTP;;
NEMO-RELATED PROTEIN; NRP;;
GLC1E GENE
*FIELD* TX

CLONING

Li et al. (1998) used the adenovirus E3-14.7K protein to screen a HeLa
cell cDNA library to search for interacting proteins in the yeast
2-hybrid system. They identified a protein, which they named FIP2
(14.7K-interacting protein) with multiple leucine zipper domains. Li et
al. (1998) identified 3 major mRNA forms of FIP2 in multiple human
tissues and found that expression of the transcripts was induced by
TNF-alpha (191160) treatment in a time-dependent manner in 2 different
cell lines. They concluded that FIP2 is one of the cellular targets for
adenovirus E3-14.7K and that its mechanism of affecting cell death
involves the TNF receptor (191190), RIP (603453), or a downstream
molecule affected by either of these 2 molecules.

Moreland et al. (2000) cloned the same gene, which they called
transcription factor IIIA-interacting protein. The rat TF3A-intP has 85%
identity with the human sequence, including 100% identity over a
leucine-rich, 36-amino acid stretch. The full-length 617-amino acid
protein has a molecular mass of 70.6 kD, numerous leucine zippers and
other leucine-rich regions, and contains a potential cys2-his-cys zinc
finger at residues 553-582.

Schwamborn et al. (2000) also cloned the optineurin gene, which they
called NRP (NEMO-related protein), by searching databases for cDNAs with
strong homology to NEMO (300248). They determined that NRP is a 67-kD
protein with 53% amino acid identity to NEMO and that it is present in a
novel high molecular weight complex that contains none of the known
members of the IKK complex. They demonstrated that de novo expression of
NRP can be induced by interferon and TNF-alpha and that these 2 stimuli
have a synergistic effect on NRP expression. They further demonstrated
that NRP is associated with the Golgi apparatus.

Li et al. (1998) found gene expression of FIP2 in heart, brain,
placenta, liver, skeletal muscle, kidney, and pancreas. By RT-PCR,
Rezaie et al. (2002) found further expression in human trabecular
meshwork, nonpigmented ciliary epithelium, retina, brain, adrenal
cortex, liver, fetus, lymphocyte, and fibroblast. Northern blot analysis
revealed a major 2.0-kb transcript in human trabecular meshwork and
nonpigmented ciliary epithelium and a minor 3.6-kb message that was 3 to
4 times less abundant. Optineurin expression was also detected in
aqueous humor samples of human, macaque, cow, pig, goat, sheep, cat, and
rabbit, suggesting that it is a secreted protein. Rezaie et al. (2002)
showed by immunocytochemistry that optineurin is localized to the Golgi
apparatus.

Wild et al. (2011) reported that the 577-amino acid human OPTN protein
contains an N-terminal coiled-coil domain, followed by an LC3 (MAP1LC3A;
601242)-interacting motif (LIR), 2 more coiled-coil domains, a
ubiquitin-binding motif (UBAN), and a C-terminal zinc finger domain.

GENE FUNCTION

Optineurin has been shown to interact with huntingtin (HTT; 613004)
(Faber et al., 1998), transcription factor IIIA (Moreland et al., 2000),
and RAB8 (165040) (Hattula and Peranen, 2000).

Rezaie et al. (2002) found that the optineurin gene is mutated in
adult-onset primary open angle glaucoma (POAG; 137760). Linkage analysis
had shown that a locus for POAG resided on chromosome 10p15-p14
(Sarfarazi et al., 1998). Optineurin was a logical candidate gene on the
basis of its physical location on chromosome 10 and its expression in
retina.

Vittitow and Borras (2002) studied the effect of glaucomatous insults on
the expression of OPTN in human eyes maintained in organ culture.
Sustained elevated intraocular pressure, TNF-alpha exposure, and
prolonged dexamethasone treatment all significantly upregulated OPTN
expression. Vittitow and Borras (2002) concluded that these results
support the protective role of OPTN in the trabecular meshwork.

Chalasani et al. (2007) explored functional features of optineurin and
its mutants. The E50K mutation (602432.0001) acquired the ability to
induce cell death selectively in retinal ganglion cells. This cell death
was mediated by oxidative stress.

Park et al. (2007) studied the relationship between 2 glaucoma-related
genes, OPTN and MYOC (601652). MYOC overexpression had no effect on OPTN
expression, but OPTN overexpression upregulated endogenous MYOC in human
trabecular meshwork cells. This induction was also observed in other
ocular and nonocular cell types, including rat PC12 pheochromocytoma
cells. Endogenous levels of both Optn and Myoc were increased in PC12
cells following NGF (see 162030)-induced neuronal differentiation.
Overexpressed OPTN, which localized to the cytoplasm, prolonged the
turnover rate of MYOC mRNA, but it had little effect on MYOC promoter
activity. Park et al. (2007) concluded that OPTN has a role in
stabilizing MYOC mRNA.

Li et al. (2008) showed that TNF-alpha, which is found in cystic fluid
of humans with autosomal dominant polycystic kidney disease (ADPKD; see
173900), disrupted the localization of polycystin-2 (PKD2; 173910) to
the plasma membrane and primary cilia through the TNF-alpha-induced
scaffold protein FIP2. Treatment of mouse embryonic kidney organ
cultures with TNF-alpha resulted in cyst formation, and this effect was
exacerbated in Pkd2 +/- kidneys. TNF-alpha also stimulated cyst
formation in vivo in Pkd2 +/- mice, and treatment of Pkd2 +/- mice with
a TNF-alpha inhibitor prevented cyst formation.

Using yeast 2-hybrid screens, Morton et al. (2008) identified TANK
(603893)-binding kinase-1 (TBK1; 604834) as a binding partner for
optineurin; the interaction was confirmed by
overexpression/immunoprecipitation experiments in HEK293 cells and by
coimmunoprecipitation of endogenous OPTN and TBK1 from cell extracts. A
TBK1-binding site was detected between residues 1 and 127 of optineurin;
residues 78 through 121 were found to display striking homology to the
TBK1-binding domain of TANK. The OPTN-binding domain was localized to
residues 601 to 729 of TBK1; residues 1 to 688 of TBK1, which do not
bind to TANK, did not interact with OPTN. The E50K OPTN mutant
(602432.0001), known to cause open angle glaucoma (GLC1E; 137760),
displayed markedly enhanced binding to TBK1, suggesting that this
interaction may contribute to familial glaucoma caused by this mutation.

Wild et al. (2011) reported that phosphorylation of human OPTN promoted
selective autophagy of ubiquitin-coated cytosolic Salmonella enterica.
Phosphorylation on ser177 by TBK1 (604834) enhanced LC3 binding affinity
and autophagic clearance of cytosolic Salmonella. On the other hand,
ubiquitin- or LC3-binding mutants of OPTN or silencing of OPTN or TBK1
impaired Salmonella autophagy, leading to increased intracellular
bacterial proliferation. Wild et al. (2011) proposed that
phosphorylation of autophagy receptors, such as OPTN, may be a general
mechanism for regulation of cargo-selective autophagy.

GENE STRUCTURE

Rezaie et al. (2002) reported that the optineurin gene contains 3
noncoding exons in the 5-prime untranslated region and 13 exons that
code for a 577-amino acid protein. Alternative splicing at the 5-prime
UTR generates at least 3 different isoforms, but all have the same
reading frame. The mouse Optn gene codes for a 584-amino acid protein
(67 kD) that has 78% identity with human optineurin.

MAPPING

The International Radiation Hybrid Mapping Consortium mapped the OPTN
gene to chromosome 10 (TMAP stSG3281).

MOLECULAR GENETICS

- Primary Open Angle Glaucoma

In patients with adult-onset primary open angle glaucoma (GLC1E;
137760), Rezaie et al. (2002) identified heterozygous mutations in the
OPTN gene (602432.0001-602432.0004). One of the mutations (602432.0004)
was also found to be associated with normal tension glaucoma
(602432.0004).

Because normal tension glaucoma (NTG) is the most frequent form of
glaucoma in Japan, Tang et al. (2003) sought mutations in the OPTN gene
in 148 unrelated Japanese patients with NTG as well as 165 patients with
POAG and 196 unrelated controls without glaucoma. No disease-causing
mutations were identified in these individuals.

Funayama et al. (2004) demonstrated that the OPTN gene was associated
with POAG rather than NTG in Japanese. Their statistical analyses showed
a possible interaction between polymorphisms in the OPTN and the tumor
necrosis factor-alpha (TNF; 191160) genes that would increase the risk
for the development and probably the progression of glaucoma in Japanese
patients with POAG.

- Amyotrophic Lateral Sclerosis

Maruyama et al. (2010) identified 2 different homozygous null mutations
in the OPTN gene, one a deletion of exon 5 (602432.0005) and the other a
nonsense mutation (602432.0006) in 4 Japanese individuals with autosomal
recessive amyotrophic lateral sclerosis (ALS12; 613435). These mutations
were not identified in over 6,800 individuals with glaucoma. In
addition, Maruyama et al. (2010) identified a missense mutation, E478G
(602432.0007), segregating as an apparently autosomal dominant mutation
with incomplete penetrance in 2 families. This mutation was not seen in
a total of 5,000 Japanese chromosomes. In cell transfection assays,
Maruyama et al. (2010) observed that nonsense and missense mutations of
OPTN abolished the inhibition of activation of nuclear factor kappa-B
(NFKB; see 164011) and that E478G mutant OPTN had a cytoplasmic
distribution different from that of wildtype OPTN or OPTN carrying a
mutation causing in POAG. A case with the E478G mutation showed
OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP43 (605078)-
or SOD1 (147450)-positive inclusions in sporadic and familial cases of
ALS were also noticeably immunolabeled by anti-OPTN antibodies.

Deng et al. (2011) observed OPTN-immunoreactive skeinlike inclusions in
anterior horn neurons and neurites in spinal cord sections from all 32
patients with sporadic ALS and in all 8 patients with familial ALS who
did not have mutations in the SOD1 gene. OPTN immunoreactivity was
absent in all 6 cases of familial ALS due to SOD1 mutations and in
tissue from 2 mouse models of ALS due to Sod1 mutations. The findings
suggested that OPTN may play a role in the pathogenesis of non-SOD1 ALS,
and that SOD1-linked ALS has a distinct disease pathogenesis.

- Paget Disease of Bone

For discussion of a possible association of variation in the OPTN gene
with susceptibility to Paget disease of bone, see 602080.

ANIMAL MODEL

Chi et al. (2010) described the phenotypic characteristics of transgenic
mice overexpressing wildtype or mutated optineurin. Mutations E50K
(602432.0001), H486R, and Optn with a deletion of the first or second
leucine zipper were used for overexpression. After 16 months, histologic
abnormalities were exclusively observed in the retina of E50K mutant
mice, with loss of retinal ganglion cells and connecting synapses in the
peripheral retina, thinning of the nerve fiber layer at the optic nerve
head at normal intraocular pressure, and massive apoptosis and
degeneration of the entire retina. Introduction of the E50K mutation
disrupted the interaction between Optn and Rab8 GTPase (RAB8A; 165040),
a protein involved in the regulation of vesicle transport from Golgi to
plasma membrane. Wiltype Optn and an active GTP-bound form of Rab8
colocalized to the Golgi. Chi et al. (2010) concluded that alteration of
the Optn sequence can initiate significant retinal degeneration in mice.

*FIELD* AV
.0001
GLAUCOMA 1, OPEN ANGLE, E
OPTN, GLU50LYS

In affected members of a family segregating adult-onset open angle
glaucoma (137760), Rezaie et al. (2002) identified a 458G-A transition
in the OPTN gene, resulting in a glu50-to-lys substitution. This
mutation was observed in 7 of 52 families, accounting for 13.5% of the
disease-causing alterations, and was not identified in any of 540 normal
chromosomes tested.

Rezaie et al. (2002) noted that 31 (81.6%) of the 38 glaucoma patients
carrying the recurrent E50K mutation had normal intraocular pressure
(IOP), ranging from 11 to 21 mm Hg, whereas the remaining 7 patients had
elevated IOP (23 to 26 mm Hg).

.0002
GLAUCOMA 1, OPEN ANGLE, E
OPTN, 2-BP INS, 691AG

In 1 of 46 families segregating adult-onset primary open angle glaucoma
(137760), Rezaie et al. (2002) identified a frameshift mutation in exon
6 of the OPTN gene, an insertion of AG between nucleotides 691 and 692.
This mutation was observed in 2.2% of the families studied and was not
seen in any of 200 normal chromosomes tested.

.0003
GLAUCOMA 1, OPEN ANGLE, E
OPTN, ARG545GLN

In 1 of 46 families segregating adult-onset primary open angle glaucoma
(137760), Rezaie et al. (2002) identified a 1944G-A transition in exon
16 of the OPTN gene, resulting in an arg545-to-glu substitution. This
mutation was not identified in any of 100 normal chromosomes tested.

.0004
GLAUCOMA, NORMAL TENSION, SUSCEPTIBILITY TO
GLAUCOMA 1, OPEN ANGLE, E, INCLUDED
OPTN, MET98LYS

Within a group of 169 subjects with adult-onset open angle glaucoma
(137760), Rezaie et al. (2002) identified a 603T-A transversion in exon
5 of the OPTN gene, resulting in a met98-to-lys substitution in 8 of 45
familial (17.8%) and 15 of 124 (12.1%) sporadic individuals with
glaucoma. Most of these individuals had normal intraocular pressure
(606657) and were screened for sequence changes in exon 5 only. This
mutation was also identified in 9 of 422 normal chromosomes, giving the
overall identification in an at-risk population of 13.6% versus 2.1% in
the general population, and making this a risk-associated alteration.

.0005
AMYOTROPHIC LATERAL SCLEROSIS 12
OPTN, DEL EXON 5

In 2 sibs with autosomal recessive ALS (ALS12; 613435) from a
consanguineous Japanese family, Maruyama et al. (2010) identified
homozygosity for deletion of exon 5 of the OPTN gene. The deletion
resulted from an Alu-mediated recombination.

.0006
AMYOTROPHIC LATERAL SCLEROSIS 12
OPTN, GLN398TER

In a Japanese woman with ALS (ALS12; 613435) who was the child of a
consanguineous union, Maruyama et al. (2010) identified a homozygosity
for a C-to-T transition at nucleotide 1502 of the OPTN gene, resulting
in a glutamine-to-nonsense substitution at codon 398 (Q398X). In a
separate analysis, Maruyama et al. (2010) found this mutation in
homozygosity in an apparently sporadic case. The probands of the 2
families were not related according to their family history but were
found to share haplotypes for a 0.9-Mb region around the OPTN gene,
suggesting that inheritance of the mutation from a common ancestor was
likely. This mutation was not detected in 781 healthy Japanese
volunteers as well as in over 6,800 individuals enrolled in glaucoma
studies, where the entire coding region of the gene was sequenced.

.0007
AMYOTROPHIC LATERAL SCLEROSIS 12
OPTN, GLU478GLY

In 4 individuals with ALS (ALS12; 613435) from 2 families, Maruyama et
al. (2010) identified a heterozygous missense mutation in the OPTN gene,
an A-to-G transition at nucleotide 1743 in exon 14 resulting in a
glutamic acid-to-glycine substitution at codon 478 (E478G). Two of the
subjects were sisters, and the pedigree suggested that the mutation
resulted in an autosomal dominant trait with incomplete penetrance. In
the second family, the sibs were brothers. Although the 2 families were
not known to be related, all affected individuals shared their haplotype
for 2.3 megabases on chromosome 10 around the OPTN gene.

*FIELD* RF
1. Chalasani, M. L.; Radha, V.; Gupta, V.; Agarwal, N.; Balasubramanian,
D.; Swarup, G.: A glaucoma-associated mutant of optineurin selectively
induces death of retinal ganglion cells which is inhibited by antioxidants. Invest.
Ophthal. Vis. Sci. 48: 1607-1614, 2007.

2. Chi, Z.-L.; Akahori, M.; Obazawa, M.; Minami, M.; Noda, T.; Nakaya,
N.; Tomarev, S.; Kawase, K.; Yamamoto, T.; Noda, S.; Sasaoka, M.;
Shimazaki, A.; Takada, Y.; Iwata, T.: Overexpression of optineurin
E50K disrupts Rab8 interaction and leads to a progressive retinal
degeneration in mice. Hum. Molec. Genet. 19: 2606-2615, 2010.

3. Deng, H.-X.; Bigio, E. H.; Zhai, H.; Fecto, F.; Ajroud, K.; Shi,
Y.; Yan, J.; Mishra, M.; Ajroud-Driss, S.; Heller, S.; Sufit, R.;
Siddique, N.; Mugnaini, E.; Siddique, T.: Differential involvement
of optineurin in amyotrophic lateral sclerosis with or without SOD1
mutations. Arch. Neurol. 68: 1057-1061, 2011.

4. Faber, P. W.; Barnes, G. T.; Srinidhi, J.; Chen, J.; Gusella, J.
F.; MacDonald, M. E.: Huntingtin interacts with a family of WW domain
proteins. Hum. Molec. Genet. 7: 1463-1474, 1998.

5. Funayama, T.; Ishikawa, K.; Ohtake, Y.; Tanino, T.; Kurasaka, D.;
Kimura, I.; Suzuki, K.; Ideta, H.; Nakamoto, K.; Yasuda, N.; Fujimaki,
T.; Murakami, A.; and 12 others: Variants in optineurin gene and
their association with tumor necrosis factor-alpha polymorphisms in
Japanese patients with glaucoma. Invest. Ophthal. Vis. Sci. 45:
4359-4367, 2004.

6. Hattula, K.; Peranen, J.: FIP-2, a coiled-coil protein, links
huntingtin to Rab8 and modulates cellular morphogenesis. Curr. Biol. 10:
1603-1606, 2000.

7. Li, X.; Magenheimer, B. S.; Xia, S.; Johnson, T.; Wallace, D. P.;
Calvet, J. P.; Li, R.: A tumor necrosis factor-alpha-mediated pathway
promoting autosomal dominant polycystic kidney disease. Nature Med. 14:
863-868, 2008.

8. Li, Y.; Kang, J.; Horwitz, M. S.: Interaction of an adenovirus
E3 14.7-kilodalton protein with a novel tumor necrosis factor alpha-inducible
cellular protein containing leucine zipper domains. Molec. Cell.
Biol. 18: 1601-1610, 1998.

9. Maruyama, H.; Morino, H.; Ito, H.; Izumi, Y.; Kato, H.; Watanabe,
Y.; Kinoshita, Y.; Kamada, M.; Nodera, H.; Suzuki, H.; Komure, O.;
Matsuura, S.; and 15 others: Mutations of optineurin in amyotrophic
lateral sclerosis. Nature 465: 223-226, 2010.

10. Moreland, R. J.; Dresser, M. E.; Rodgers, J. S.; Roe, B. A.; Conaway,
J. W.; Conaway, R. C.; Hanas, J. S.: Identification of a transcription
factor IIIA-interacting protein. Nucleic Acids Res. 28: 1986-1993,
2000.

11. Morton, S.; Hesson, L.; Peggie, M.; Cohen, P.: Enhanced binding
of TBK1 by an optineurin mutant that causes a familial form of primary
open angle glaucoma. FEBS Lett. 582: 997-1002, 2008.

12. Park, B.-C.; Tibudan, M.; Samaraweera, M.; Shen, X.; Yue, B. Y.
J. T.: Interaction between two glaucoma genes, optineurin and myocilin. Genes
Cells 12: 969-979, 2007.

13. Rezaie, T.; Child, A.; Hitchings, R.; Brice, G.; Miller, L.; Coca-Prados,
M.; Heon, E.; Krupin, T.; Ritch, R.; Kreutzer, D.; Crick, R. P.; Sarfarazi,
M.: Adult-onset primary open-angle glaucoma caused by mutations in
optineurin. Science 295: 1077-1079, 2002.

14. Sarfarazi, M.; Child, A.; Stoilova, D.; Brice, G.; Desai, T.;
Trifan, O. C.; Poinoosawmy, D.; Crick, R. P.: Localization of the
fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to
the 10p15-p14 region. Am. J. Hum. Genet. 62: 641-652, 1998.

15. Schwamborn, K.; Weil, R.; Courtois, G.; Whiteside, S. T.; Israel,
A.: Phorbol esters and cytokines regulate the expression of the NEMO-related
protein, a molecule involved in a NF-kappa-B-independent pathway. J.
Biol. Chem. 275: 22780-22789, 2000.

16. Tang, S.; Toda, Y.; Kashiwagi, K.; Mabuchi, F.; Iijima, H.; Tsukahara,
S.; Yamagata, Z.: The association between Japanese primary open-angle
glaucoma and normal tension glaucoma patients and the optineurin gene. Hum.
Genet. 113: 276-279, 2003.

17. Vittitow, J. L.; Borras, T.: Expression of optineurin, a glaucoma-linked
gene, is influenced by elevated intraocular pressure. Biochem. Biophys.
Res. Commun. 298: 67-74, 2002.

18. Wild, P.; Farhan, H.; McEwan, D. G.; Wagner, S.; Rogov, V. V.;
Brady, N. R.; Richter, B.; Korac, J.; Waidmann, O.; Choudhary, C.;
Dotsch, V.; Bumann, D.; Dikic, I.: Phosphorylation of the autophagy
receptor optineurin restricts Salmonella growth. Science 333: 228-233,
2011.

*FIELD* CN
George E. Tiller - updated: 8/20/2013
Marla J. F. O'Neill - updated: 3/27/2013
Cassandra L. Kniffin - updated: 3/14/2013
Matthew B. Gross - updated: 8/19/2011
Paul J. Converse - updated: 8/19/2011
Ada Hamosh - updated: 6/2/2010
Patricia A. Hartz - updated: 8/15/2008
Patricia A. Hartz - updated: 6/3/2008
Jane Kelly - updated: 9/25/2007
Jane Kelly - updated: 6/23/2005
Victor A. McKusick - updated: 8/13/2003
Patricia A. Hartz - updated: 12/16/2002
Ada Hamosh - reorganized: 2/13/2002
Ada Hamosh - updated: 2/13/2002

*FIELD* CD
Victor A. McKusick: 3/10/1998

*FIELD* ED
carol: 08/21/2013
tpirozzi: 8/21/2013
carol: 8/20/2013
tpirozzi: 8/20/2013
carol: 3/27/2013
terry: 3/27/2013
carol: 3/18/2013
ckniffin: 3/14/2013
mgross: 8/19/2011
terry: 8/19/2011
alopez: 7/13/2010
alopez: 6/8/2010
terry: 6/2/2010
wwang: 9/15/2009
mgross: 8/19/2008
terry: 8/15/2008
mgross: 6/12/2008
terry: 6/3/2008
carol: 9/25/2007
carol: 10/25/2006
alopez: 6/23/2005
tkritzer: 8/19/2003
terry: 8/13/2003
carol: 5/13/2003
mgross: 12/18/2002
terry: 12/16/2002
cwells: 9/11/2002
ckniffin: 3/12/2002
carol: 2/14/2002
carol: 2/13/2002
terry: 2/13/2002
carol: 2/12/2002
terry: 1/25/2002
dholmes: 3/30/1998
alopez: 3/10/1998

MIM 606657
*RECORD*
*FIELD* NO
606657
*FIELD* TI
#606657 GLAUCOMA, NORMAL TENSION, SUSCEPTIBILITY TO
;;NTG;;
GLAUCOMA, NORMAL PRESSURE, SUSCEPTIBILITY TO; NPG
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
susceptibility to normal tension glaucoma is associated with a
particular intronic polymorphism of the optic atrophy-1 gene (OPA1;
605290) and mutation in the OPTN gene (602432).

CLINICAL FEATURES

Glaucoma is the second most common cause of blindness worldwide
(Thylefors et al., 1995; Quigley, 1996). It is characterized by
progressive loss of optic nerve axons and visual field damage. Most
glaucoma in Caucasian and African American populations is of the primary
open angle glaucoma (POAG) type (see 137760), in which elevated
intraocular pressure (IOP) is a major feature (Sommer et al., 1991).
Normal tension glaucoma (NTG) is an important subtype of POAG, in which
the IOP is consistently within the statistically normal population
range. NTG accounts for approximately one-third of all POAG cases
(Bonomi et al., 1998). Because the IOP is normal when measured and
patients often have good central vision, NTG is underdiagnosed and the
condition presents late.

BIOCHEMICAL FEATURES

Yang et al. (2001) analyzed T-cell subsets and levels of cytokine IL2
(147680) and soluble IL2 receptor (see, e.g., 147730) in the peripheral
blood of patients with normal pressure glaucoma and primary open angle
glaucoma and compared them to values in age-matched controls. They found
increased frequency of CD8+/HLA-DR+ lymphocytes in patients with NPG and
increased CD3+/CD8+ lymphocytes in both NPG and POAG patients. CD5+
lymphocytes were higher only in POAG patients. The mean concentration of
soluble IL2R was higher in NPG and POAG patients than in controls
although the IL2 concentration was similar in patients and controls.
Also, the reactivity of T lymphocytes to the nonspecific reagent
phytohemagglutinin was reduced significantly in both NPG and POAG
patients. The authors concluded that the immune system might play an
important role in initiation or progression of glaucomatous optic
neuropathy in some patients.

MOLECULAR GENETICS

- Association with OPA1

Because different mutations in the same gene may cause widely different
phenotypes and because autosomal dominant optic atrophy (165500) due to
mutation in the OPA1 gene shows a similar optic neuropathy in the
absence of raised IOP, Aung et al. (2002) hypothesized that the OPA1
gene represents an excellent candidate gene for NTG. In a study of 2
cohorts of NTG patients, they found a strong association with a
combination of 2 single nucleotide polymorphisms (SNPs) in intron 8 of
the OPA1 gene (605290.0010).

In 137 patients with primary open angle glaucoma (POAG), including 67
with high tension glaucoma (HTG) and 70 with NTG, and 75 controls from
the northeast of England, Yu-Wai-Man et al. (2010) analyzed 3 SNPs in
the OPA1 gene and found significant association between the T allele at
IVS8+4C-T and the risk of developing NTG (odds ratio, 2.04; p = 0.004)
but not HTG. Logistic regression analysis confirmed a strong association
between the CT/TT compound genotype at IVS8+4 and IVS8+32 with NTG (OR,
29.75; p = 0.001). Yu-Wai-Man et al. (2010) concluded that the CT/TT
compound genotype in intron 8 of the OPA1 gene is a strong genetic risk
determinant for NTG but not HTG.

- Association with OPTN

Rezaie et al. (2002) identified a missense mutation (602432.0004) in the
OPTN gene resulting in susceptibility to normal tension glaucoma.

*FIELD* RF
1. Aung, T.; Ocaka, L.; Ebenezer, N. D.; Morris, A. G.; Krawczak,
M.; Thiselton, D. L.; Alexander, C.; Votruba, M.; Brice, G.; Child,
A. H.; Francis, P. J.; Hitchings, R. A.; Lehmann, O. J.; Bhattacharya,
S. S.: A major marker for normal tension glaucoma: association with
polymorphisms in the OPA1 gene. Hum. Genet. 110: 52-56, 2002.

2. Bonomi, L.; Marchini, G.; Marraffa, M.; Bernardi, P.; De Franco,
I.; Perfetti, S.; Varotto, A.; Tenna, V.: Prevalence of glaucoma
and intraocular pressure distribution in a defined population: the
Egna-Neumarkt study. Ophthalmology 105: 209-215, 1998.

3. Quigley, H. A.: Number of people with glaucoma worldwide. Brit.
J. Ophthal. 80: 389-393, 1996.

4. Rezaie, T.; Child, A.; Hitchings, R.; Brice, G.; Miller, L.; Coca-Prados,
M.; Heon, E.; Krupin, T.; Ritch, R.; Kreutzer, D.; Crick, R. P.; Sarfarazi,
M.: Adult-onset primary open-angle glaucoma caused by mutations in
optineurin. Science 295: 1077-1079, 2002.

5. Sommer, A.; Tielsch, J. M.; Katz, J.; Quigley, H. A.; Gottsch,
J. D.; Javitt, J.; Singh, K.: Relationship between intraocular pressure
and primary open angle glaucoma among white and black Americans: the
Baltimore Eye Survey. Arch. Ophthal. 109: 1090-1095, 1991.

6. Thylefors, B.; Negrel, A.-D.; Pararajasegaram, R.; Dadzie, K. Y.
: Global data on blindness. Bull. WHO 73: 115-121, 1995.

7. Yang, J.; Patil, R. V.; Yu, H.; Gordon, M.; Wax, M. B.: T cell
subsets and sIL-2R/IL-2 levels in patients with glaucoma. Am. J.
Ophthal. 131: 421-426, 2001.

8. Yu-Wai-Man, P.; Stewart, J. D.; Hudson, G.; Andrews, R. M.; Griffiths,
P. G.; Birch, M. K.; Chinnery, P. F.: OPA1 increases the risk of
normal but not high tension glaucoma. J. Med. Genet. 47: 120-125,
2010.

*FIELD* CN
Marla J. F. O'Neill - updated: 8/25/2010
Ada Hamosh - updated: 2/13/2002

*FIELD* CD
Victor A. McKusick: 1/30/2002

*FIELD* ED
wwang: 08/26/2010
terry: 8/25/2010
ckniffin: 10/27/2004
terry: 6/27/2002
carol: 2/13/2002
carol: 1/30/2002

MIM 613435
*RECORD*
*FIELD* NO
613435
*FIELD* TI
#613435 AMYOTROPHIC LATERAL SCLEROSIS 12; ALS12
*FIELD* TX
A number sign (#) is used with this entry because this form of
read moreamyotrophic lateral sclerosis can be caused by homozygous or
heterozygous mutation in the optineurin gene (OPTN; 602432) on
chromosome 10p15-p14 and can manifest an autosomal recessive, autosomal
dominant, or sporadic inheritance pattern.

Primary open angle glaucoma-1E (POAG; see 137760) is an allelic disorder
caused by distinct missense mutations and segregating in an autosomal
dominant manner.

For a general phenotypic description and discussion of genetic
heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).

CLINICAL FEATURES

Of 6 Japanese individuals from consanguineous marriages who had ALS,
Maruyama et al. (2010) identified 3 with mutations in the OPTN gene. Two
were sibs. One member of the sib pair developed muscle weakness of her
left arm at 33 years of age that progressed to dysphagia requiring
endotracheal intubation. She was bedridden by age 34 and died at age 57.
Her brother also had onset with left arm weakness at 36 years of age and
1 year later developed dysphagia, dysarthria, and tongue fasciculations.
He likewise required endotracheal intubation, was bedridden by age 37,
and died at the age of 55. The third patient from a consanguineous
family developed dysarthria at 52 years of age and had muscle weakness
of her left upper and lower extremities starting at 54 years of age. Her
deep tendon reflex was exaggerated, but there was no pathologic reflex.
She was still breathing independently at 60 years of age. These 3
individuals were homozygous for mutation in OPTN; 4 other heterozygous
individuals identified in a separate analysis had onset in their 50s
with slow progression. All individuals with mutations of OPTN showed
onset from 30 to 60 years of age. Most of them showed a relatively slow
progression and long duration before respiratory failure, although the
clinical phenotypes were not homogeneous.

MAPPING

Using homozygosity mapping in 4 Japanese subjects from consanguineous
marriages with ALS, Maruyama et al. (2010) identified a candidate region
for the disorder on chromosome 10 containing 17 genes.

MOLECULAR GENETICS

Among 8 Japanese patients with ALS, Maruyama et al. (2010) identified
homozygosity for 2 null mutations in the OPTN gene, one a deletion of
exon 5 (602432.0005) in 2 sibs and the other a nonsense mutation (Q398X;
602432.0006) in 2 individuals thought to be unrelated but who shared a
haplotype for a 0.9-Mb region containing the OPTN gene. The authors also
identified heterozygosity for a missense mutation (E478G; 602432.0007)
within the OPTN ubiquitin-binding domain in 4 individuals from 2
families. The pedigree of one of these families suggested that the
disorder is an autosomal dominant trait with incomplete penetrance.
Although these 2 families were not known to be related, all affected
individuals shared their haplotype for 2.3 Mb on chromosome 10 around
the OPTN gene. Neither the Q398X nor the E478G mutations were observed
in 781 healthy Japanese volunteers or in over 6,800 (including 1,728
Japanese) individuals in glaucoma studies, in which the entire coding
region of the gene was investigated. Collectively, the mutation was
absent over a total of 5,000 Japanese chromosomes. The deletion mutation
was also absent in 200 Japanese, and not reported in the over 6,800
glaucoma individuals.

PATHOGENESIS

In cell transfection assays, Maruyama et al. (2010) observed that
nonsense and missense mutations of OPTN abolished the inhibition of
activation of nuclear factor kappa-B (NFKB; see 164011) and that E478G
(602432.0007) mutant OPTN had a cytoplasmic distribution different from
that of wildtype OPTN or OPTN carrying a mutation resulting in primary
open angle glaucoma (POAG; see 137760). A case with the E478G mutation
showed OPTN-immunoreactive cytoplasmic inclusions. Furthermore, TDP43
(605078)- or SOD1 (147450)-positive inclusions in sporadic and familial
cases of ALS were also noticeably immunolabeled by anti-OPTN antibodies.

*FIELD* RF
1. Maruyama, H.; Morino, H.; Ito, H.; Izumi, Y.; Kato, H.; Watanabe,
Y.; Kinoshita, Y.; Kamada, M.; Nodera, H.; Suzuki, H.; Komure, O.;
Matsuura, S.; and 15 others: Mutations of optineurin in amyotrophic
lateral sclerosis. Nature 465: 223-226, 2010.

*FIELD* CD
Ada Hamosh: 6/8/2010

*FIELD* ED
alopez: 06/08/2010