Alternative titles; symbols
HGNC Approved Gene Symbol: OPTN
Cytogenetic location: 10p13 Genomic coordinates (GRCh38): 10:13,100,082-13,138,308 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p13 | {Glaucoma, normal tension, susceptibility to} | 606657 | 3 | |
| Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia | 613435 | Autosomal dominant; Autosomal recessive | 3 | |
| Glaucoma 1, open angle, E | 137760 | Autosomal dominant | 3 |
Optineurin is an adaptor protein that interacts with numerous proteins. It is involved in regulating many cellular functions, including vesicular trafficking from the Golgi to plasma membrane, endocytic trafficking, and signaling leading to NF-kappa-B (see 164011) activation (summary by Vaibhava et al., 2012).
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.
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.
Vaibhava et al. (2012) found that optineurin interacted with TBC1D17 (616659), a GTPase-activating protein for RAB8. Overexpression, knockdown, and mutation analyses revealed that optineurin was required to mediate interaction between TBC1D17 and RAB8. The E50K optineurin mutation enhanced inhibition of RAB8 by TBC1D17, resulting in defective endocytotic recycling of transferrin receptor (TFRC 190010) and loss of recruitment of RAB8 to endocytic recycling tubules.
Lazarou et al. (2015) used genome editing to knock out 5 autophagy receptors in HeLa cells and demonstrated that 2 receptors previously linked to xenophagy, NDP52 (604587) and optineurin, are the primary receptors for PINK1 (608309)- and parkin (602544)-mediated mitophagy. PINK1 recruits NDP52 and optineurin but not p62 (SQSTM1; 601530) to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1 (603168), DFCP1 (ZNFN2A1; 605471), and WIPI1 (609224) to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3 (MAP1LC3A; 601242). Lazarou et al. (2015) concluded that their observations support a model in which PINK1-generated phosph-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal.
Ito et al. (2016) found that OPTN actively suppressed receptor-interacting kinase-1 (RIPK1; 603453)-dependent signaling by regulating its turnover. Loss of OPTN led to progressive dysmyelination and axonal degeneration through engagement of necroptotic machinery in the CNS, including RIPK1, RIPK3 (605817), and mixed lineage kinase domain-like protein (MLKL; 615153). Furthermore, RIPK1- and RIPK3-mediated axonal pathology was commonly observed in SOD1(G93A) (147450.0008) transgenic mice and pathologic samples from human ALS patients. Thus, RIPK1 and RIPK3 play a critical role in mediating progressive axonal degeneration.
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.
Stumpf (2023) mapped the OPTN gene to chromosome 10p13 based on an alignment of the OPTN sequence (GenBank BC032762) with the genomic sequence (GRCh38).
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 12 with or without Frontotemporal Dementia
Maruyama et al. (2010) identified 2 different homozygous null mutations in the OPTN gene, a deletion of exon 5 (602432.0005) and a nonsense mutation (602432.0006), in 4 Japanese individuals with autosomal recessive amyotrophic lateral sclerosis-12 (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 patient 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 patients with 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.
In a deceased patient (case A) with frontotemporal dementia (FTD), Pottier et al. (2015) identified compound heterozygous mutations in the OPTN gene (Q235X and A481V). The patient had no obvious features of motor neuron disease. The mutations, which were found by whole-genome sequencing, were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases. OPTN protein levels were dramatically reduced in patient cerebellum, consistent with a loss of function. Levels of TBK1 (604834) were also decreased compared to controls.
In a Chinese woman with rapidly progressive ALS12 with frontotemporal dementia, Feng et al. (2019) identified a heterozygous missense mutation in the OPTN gene (E516Q; 602432.0008). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was present at a low frequency in the ExAC database (2.5 x 10(-5)). Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as likely pathogenic by ACMG criteria.
Associations Pending Confirmation
For discussion of a possible association of variation in the OPTN gene with susceptibility to Paget disease of bone, see 167250.
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. Wildtype 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.
In affected members of a family segregating autosomal dominant adult-onset open angle glaucoma (GLC1E; 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).
In 1 of 46 families segregating autosomal dominant adult-onset primary open angle glaucoma (GLC1E; 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.
In 1 of 46 families segregating autosomal dominant adult-onset primary open angle glaucoma (GLC1E; 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.
Within a group of 169 patients with autosomal dominant adult-onset open angle glaucoma (GLC1E; 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.
In 2 sibs with autosomal recessive amyotrophic lateral sclerosis-12 (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.
In a Japanese woman with amyotrophic lateral sclerosis-12 (ALS12; 613435), whose parents were consanguineous, Maruyama et al. (2010) identified 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 or in over 6,800 individuals enrolled in glaucoma studies, where the entire coding region of the gene was sequenced.
In 4 individuals with amyotrophic lateral sclerosis-12 (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). In 1 family, 2 sisters were affected, and the pedigree suggested that the mutation resulted in an autosomal dominant trait with incomplete penetrance. In the other family, 2 brothers were affected. 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.
In a Chinese woman with amyotrophic lateral sclerosis-12 with frontotemporal dementia (ALS12; 613435), Feng et al. (2019) identified a heterozygous c.1546G-C transversion (c.1546G-C, NM_001008212.2) in exon 14 of the OPTN gene, resulting in a glu516-to-gln (E516Q) substitution at a highly conserved residue. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was present at a low frequency in the ExAC database (2.5 x 10(-5)). Functional studies of the variant and studies of patient cells were not performed, but the variant was classified as likely pathogenic by ACMG criteria. The patient had onset of frontotemporal dementia (FTD) at 38 years of age, followed by ALS. She had a rapidly progressive disease course and died of respiratory failure 18 months after disease onset. There was no family history of a similar disorder. The authors noted that the phenotypic spectrum associated with OPTN mutations may be broader and include FTD.
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