SIX6

Summary

Gene Symbol: SIX6
Description: SIX homeobox 6
Alias: MCOPCT2, ODRMD, OPTX2, Six9, homeobox protein SIX6, homeodomain protein OPTX2, optic homeobox 2, sine oculis homeobox homolog 6, sine oculis homeobox protein 6, sine oculis homeobox-like protein 6
Species: human
Products:     SIX6

Top Publications

  1. Gallardo M, Rodriguez De Cordoba S, Schneider A, Dwyer M, Ayuso C, Bovolenta P. Analysis of the developmental SIX6 homeobox gene in patients with anophthalmia/microphthalmia. Am J Med Genet A. 2004;129A:92-4 pubmed
  2. Springelkamp H, Höhn R, Mishra A, Hysi P, Khor C, Loomis S, et al. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process. Nat Commun. 2014;5:4883 pubmed publisher
    ..This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition. ..
  3. Aijaz S, Clark B, Williamson K, van Heyningen V, Morrison D, Fitzpatrick D, et al. Absence of SIX6 mutations in microphthalmia, anophthalmia, and coloboma. Invest Ophthalmol Vis Sci. 2004;45:3871-6 pubmed
    To investigate whether 173 patients with microphthalmia, anophthalmia, and coloboma have mutations in the eye-development gene SIX6.
  4. Gallardo M, Lopez Rios J, Fernaud Espinosa I, Granadino B, Sanz R, Ramos C, et al. Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Genomics. 1999;61:82-91 pubmed
    ..here the cloning and characterization of SIX6, a novel human SIX gene that is the homologue of the chick Six6(Optx2) gene. SIX6 is closely related to SIX3 and is expressed in the developing and adult human retina...
  5. Iglesias A, Springelkamp H, van der Linde H, Severijnen L, Amin N, Oostra B, et al. Exome sequencing and functional analyses suggest that SIX6 is a gene involved in an altered proliferation-differentiation balance early in life and optic nerve degeneration at old age. Hum Mol Genet. 2014;23:1320-32 pubmed publisher
    ..Previously, genome-wide significant evidence for the association of rs10483727 in SIX1-SIX6 locus with VCDR and subsequent POAG was found...
  6. Wiggs J, Yaspan B, Hauser M, Kang J, Allingham R, Olson L, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet. 2012;8:e1002654 pubmed publisher
    ..69 [95%CI 0.63-0.75], p?=?1.86×10?¹?), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR?=?1.32 [95%CI 1.21-1.43], p?=?3.87×10?¹¹)...
  7. Osman W, Low S, Takahashi A, Kubo M, Nakamura Y. A genome-wide association study in the Japanese population confirms 9p21 and 14q23 as susceptibility loci for primary open angle glaucoma. Hum Mol Genet. 2012;21:2836-42 pubmed publisher
    ..An linkage disequilibrium block containing rs10483727 includes the SIX6 gene that was implicated to have a critical role in eye development, and genes in both represented loci (SIX6 on ..
  8. Ogawa Y, Shiraki T, Asano Y, Muto A, Kawakami K, Suzuki Y, et al. Six6 and Six7 coordinately regulate expression of middle-wavelength opsins in zebrafish. Proc Natl Acad Sci U S A. 2019;: pubmed publisher
    ..These results demonstrate that in zebrafish, six6b and six7 govern expression of the SWS2 and RH2 opsins responsible for middle-wavelength sensitivity, which would be physiologically important for daylight vision. ..
  9. Shiga Y, Akiyama M, Nishiguchi K, Sato K, Shimozawa N, Takahashi A, et al. Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. Hum Mol Genet. 2018;27:1486-1496 pubmed publisher
    ..study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide ..

More Information

Publications55

  1. Ozel A, Moroi S, Reed D, Nika M, Schmidt C, Akbari S, et al. Genome-wide association study and meta-analysis of intraocular pressure. Hum Genet. 2014;133:41-57 pubmed publisher
    ..with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of ..
  2. Rong S, Lu S, Matsushita K, Huang C, Leung C, Kawashima R, et al. Association of the SIX6 locus with primary open angle glaucoma in southern Chinese and Japanese. Exp Eye Res. 2019;180:129-136 pubmed publisher
    The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese...
  3. Diacou R, Zhao Y, Zheng D, Cvekl A, Liu W. Six3 and Six6 Are Jointly Required for the Maintenance of Multipotent Retinal Progenitors through Both Positive and Negative Regulation. Cell Rep. 2018;25:2510-2523.e4 pubmed publisher
    Gene regulation of multipotent neuroretinal progenitors is partially understood. Through characterizing Six3 and Six6 double knockout retinas (DKOs), we demonstrate Six3 and Six6 are jointly required for the maintenance of multipotent ..
  4. Kuo J, Zangwill L, Medeiros F, Liebmann J, Girkin C, Hammel N, et al. Quantitative Trait Locus Analysis of SIX1-SIX6 With Retinal Nerve Fiber Layer Thickness in Individuals of European Descent. Am J Ophthalmol. 2015;160:123-30.e1 pubmed publisher
    To perform a quantitative trait locus (QTL) analysis and evaluate whether a locus between SIX1 and SIX6 is associated with retinal nerve fiber layer (RNFL) thickness in individuals of European descent...
  5. Liu Y, Du Y, Xie W, Zhang F, Forrest D, Liu C. Generation of Conditional Knockout Mice by Sequential Insertion of Two loxP Sites In Cis Using CRISPR/Cas9 and Single-Stranded DNA Oligonucleotides. Methods Mol Biol. 2019;1874:191-210 pubmed publisher
    ..In this chapter, we describe our procedures and timeline using this sequential method to make a Six6 cKO mouse line as a demonstration of its feasibility.
  6. Chen Y, Hughes G, Chen X, Qian S, Cao W, Wang L, et al. Genetic Variants Associated With Different Risks for High Tension Glaucoma and Normal Tension Glaucoma in a Chinese Population. Invest Ophthalmol Vis Sci. 2015;56:2595-600 pubmed publisher
    ..reported single nucleotide polymorphisms (SNPs) located at four gene regions (TMCO1, CDKN2B-AS1, ATOH7, and SIX1/SIX6) was genotyped...
  7. Verhoeven V, Hysi P, Wojciechowski R, Fan Q, Guggenheim J, Höhn R, et al. Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia. Nat Genet. 2013;45:314-8 pubmed publisher
    ..KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1...
  8. Mabuchi F, Sakurada Y, Kashiwagi K, Yamagata Z, Iijima H, Tsukahara S. Involvement of genetic variants associated with primary open-angle glaucoma in pathogenic mechanisms and family history of glaucoma. Am J Ophthalmol. 2015;159:437-44.e2 pubmed publisher
    ..for 5 non-IOP-related genetic variants predisposing to POAG near the SRBD1, ELOVL5, CDKN2B/CDKN2B-AS1, SIX1/SIX6, and ATOH7 genes...
  9. Xie H, Hoffmann H, Meadows J, Mayo S, Trang C, Leming S, et al. Homeodomain Proteins SIX3 and SIX6 Regulate Gonadotrope-specific Genes During Pituitary Development. Mol Endocrinol. 2015;29:842-55 pubmed publisher
    Sine oculis-related homeobox 3 (SIX3) and SIX6, 2 closely related homeodomain transcription factors, are involved in development of the mammalian neuroendocrine system and mutations of Six6 adversely affect fertility in mice...
  10. Burdon K, Mitchell P, Lee A, Healey P, White A, Rochtchina E, et al. Association of open-angle glaucoma loci with incident glaucoma in the Blue Mountains Eye Study. Am J Ophthalmol. 2015;159:31-6.e1 pubmed publisher
    ..Two loci also known to be associated with cup-to-disc ratio as well as OAG (9p21 near CDKN2B-AS1 and SIX1/SIX6) were both significantly associated with incident OAG in the Blue Mountains Eye Study cohort (P = .006 and P = ...
  11. Fish M, Nakayama T, Fisher M, Hirsch N, Cox A, Reeder R, et al. Xenopus mutant reveals necessity of rax for specifying the eye field which otherwise forms tissue with telencephalic and diencephalic character. Dev Biol. 2014;395:317-330 pubmed publisher
    ..g. pax6, lhx2 and six6) are not dependent on rax activity through neurulation...
  12. Gold K, Brand A. Optix defines a neuroepithelial compartment in the optic lobe of the Drosophila brain. Neural Dev. 2014;9:18 pubmed publisher
    ..Six3 and Six6 are required for mammalian eye and forebrain development, and mutations in humans are associated with severe eye ..
  13. Souto F, Giampietro B, Takiuti J, Campos L, Hirata C, Yamamoto J. Clinical features of paediatric uveitis at a tertiary referral centre in São Paulo, SP, Brazil. Br J Ophthalmol. 2018;: pubmed publisher
    ..Patients with incomplete medical records, previous ocular trauma, or less than six6?months of follow-up were excluded. Thirty-nine children (25 female/14 male) were included...
  14. Trikha S, Saffari E, Nongpiur M, Baskaran M, Ho H, Li Z, et al. A Genetic Variant in TGFBR3-CDC7 Is Associated with Visual Field Progression in Primary Open-Angle Glaucoma Patients from Singapore. Ophthalmology. 2015;122:2416-22 pubmed publisher
    ..Single nucleotide polymorphisms (SNPs) and their proxies from 10 POAG-associated loci (CAV1-CAV2, CDKN2B-AS1, SIX1-SIX6, an intergenic region on chromosome 8q22, ABCA1, GAS7, AFAP1, GMDS, PMM2, and TGFBR3-CDC7) identified from genome-..
  15. Wang Z, Yasugi S, Ishii Y. Chx10 functions as a regulator of molecular pathways controlling the regional identity in the primordial retina. Dev Biol. 2016;413:104-11 pubmed publisher
    ..This phenotypic change involved ectopic expression of NR transcription factor genes, Sox2, Six3, Rx1 and Optx2, which, when misexpressed, counteracted RPE development without upregulating Chx10...
  16. Singh R, Mallela R, Cornuet P, Reifler A, Chervenak A, West M, et al. Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures. Stem Cells Dev. 2015;24:2778-95 pubmed publisher
    ..found that deriving such tissue in adherent conditions robustly induces all eye field genes (RX, PAX6, LHX2, SIX3, SIX6) and produces four layers of pure populations of retinal cells: RPE (expressing NHERF1, EZRIN, RPE65, DCT, TYR, ..
  17. Abu Amero K, Kondkar A, Chalam K. An Updated Review on the Genetics of Primary Open Angle Glaucoma. Int J Mol Sci. 2015;16:28886-911 pubmed publisher
    ..single nucleotide polymorphisms (SNPs) at different loci including CAV1/CAV2, TMCO1, CDKN2B-AS1, CDC7-TGFBR3, SIX1/SIX6, GAS7 and ATOH7 to be associated with POAG and its related quantitative traits (endophenotypes)...
  18. Yoshikawa M, Nakanishi H, Yamashiro K, Miyake M, Akagi T, Gotoh N, et al. Association of Glaucoma-Susceptible Genes to Regional Circumpapillary Retinal Nerve Fiber Layer Thickness and Visual Field Defects. Invest Ophthalmol Vis Sci. 2017;58:2510-2519 pubmed publisher
    ..nucleotide polymorphisms (SNPs) of four glaucoma-susceptible genes: the CDKN2B(AS1), TMCO1, CAV1/CAV2, and SIX1/SIX6 genes...
  19. Shah M, Tabanera N, Krishnadas S, Pillai M, Bovolenta P, Sundaresan P. Identification and characterization of variants and a novel 4 bp deletion in the regulatory region of SIX6, a risk factor for primary open-angle glaucoma. Mol Genet Genomic Med. 2017;5:323-335 pubmed publisher
    ..i>SIX6 encodes a transcription factor involved in retina, optic nerve, and pituitary development...
  20. Ledford K, MARTINEZ DE LUNA R, Theisen M, Rawlins K, Viczian A, Zuber M. Distinct cis-acting regions control six6 expression during eye field and optic cup stages of eye formation. Dev Biol. 2017;426:418-428 pubmed publisher
    The eye field transcription factor, Six6, is essential for both the early (specification and proliferative growth) phase of eye formation, as well as for normal retinal progenitor cell differentiation...
  21. Zakrzewski K, JarzÄ…b M, Pfeifer A, Oczko Wojciechowska M, JarzÄ…b B, Liberski P, et al. Transcriptional profiles of pilocytic astrocytoma are related to their three different locations, but not to radiological tumor features. BMC Cancer. 2015;15:778 pubmed publisher
    ..The most prominent differences were noted for IRX2, PAX3, CXCL14, LHX2, SIX6, CNTN1 and SIX1 genes expression even within different compartments of the supratentorial region...
  22. Yoshikawa M, Yamashiro K, Nakanishi H, Miyata M, Miyake M, Hosoda Y, et al. Association of SIX1/SIX6 locus polymorphisms with regional circumpapillary retinal nerve fibre layer thickness: The Nagahama study. Sci Rep. 2017;7:4393 pubmed publisher
    SIX1 and SIX6 are glaucoma susceptibility genes. Previous reports indicate that the single nucleotide polymorphism (SNP) rs33912345 in SIX6 is associated with inferior circumpapillary retinal nerve fibre layer (cpRNFL) thickness (cpRNFLT)...
  23. Ochi H, Kawaguchi A, Tanouchi M, Suzuki N, Kumada T, Iwata Y, et al. Co-accumulation of cis-regulatory and coding mutations during the pseudogenization of the Xenopus laevis homoeologs six6.L and six6.S. Dev Biol. 2017;427:84-92 pubmed publisher
    ..We addressed this issue by investigating the evolution of duplicated homeobox genes, six6.L and six6.S, in the allotetraploid frog Xenopus laevis...
  24. Hoffmann H, Trang C, Gong P, Kimura I, Pandolfi E, Mellon P. Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility. J Neurosci. 2016;36:3506-18 pubmed publisher
    ..to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P), and able to compete with the homeoprotein SIX6 for occupation of the identified ATTA sites in the GnRH promoter...
  25. Goldsmith S, Lovell Badge R, Rizzoti K. SOX2 is sequentially required for progenitor proliferation and lineage specification in the developing pituitary. Development. 2016;143:2376-88 pubmed publisher
    ..SOX2 is known to activate expression of Six6, encoding a homeodomain transcription factor, in the ventral diencephalon...
  26. Towers C, Guarnieri A, Micalizzi D, Harrell J, Gillen A, Kim J, et al. The Six1 oncoprotein downregulates p53 via concomitant regulation of RPL26 and microRNA-27a-3p. Nat Commun. 2015;6:10077 pubmed publisher
    ..Thus, we identify a competitive mechanism of p53 regulation, which may have consequences for drugs aimed at reinstating p53 function in tumours. ..
  27. Sang J, Jia L, Zhao B, Wang H, Zhang N, Wang N. Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population. Sci China Life Sci. 2016;59:694-9 pubmed publisher
    ..association of three single nucleotide polymorphisms (SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma (POAG) in the Chinese population...
  28. Kondkar A, Azad T, Almobarak F, Kalantan H, Sultan T, Alsabaani N, et al. Polymorphism rs10483727 in the SIX1/SIX6 Gene Locus Is a Risk Factor for Primary Open Angle Glaucoma in a Saudi Cohort. Genet Test Mol Biomarkers. 2017;: pubmed publisher
    Variant rs10483727 in the SIX1/SIX6 locus has been significantly associated with primary open angle glaucoma (POAG) in multiple ethnic groups...
  29. Lopez Rios J, Gallardo M, Rodriguez De Cordoba S, Bovolenta P. Six9 (Optx2), a new member of the six gene family of transcription factors, is expressed at early stages of vertebrate ocular and pituitary development. Mech Dev. 1999;83:155-9 pubmed
    ..We report here a detailed expression analysis in chick and mouse of Six9 (Optx2), a novel gene of the Six/sine oculis family closely related to Six3...
  30. Ou Z, Martin D, Bedoyan J, Cooper M, Chinault A, Stankiewicz P, et al. Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement. Am J Med Genet A. 2008;146A:2480-9 pubmed publisher
    ..Chromosome 14q22.3-q23.3 contains 51 genes, including SIX1, SIX6, and OTX2. A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3-q24...
  31. Hu S, Mamedova A, Hegde R. DNA-binding and regulation mechanisms of the SIX family of retinal determination proteins. Biochemistry. 2008;47:3586-94 pubmed publisher
    ..In the present study we examined the DNA-binding specificity and mechanisms of Six2 and Six6 toward the Trex/MEF3 consensus sequence and the core tetranucleotide ATTA commonly recognized by homeodomain ..
  32. Liu Q, Li A, Tian Y, Liu Y, Li T, Zhang C, et al. The expression profile and clinic significance of the SIX family in non-small cell lung cancer. J Hematol Oncol. 2016;9:119 pubmed
    ..SIX4 and SIX6 were linked to the lymph node metastasis (LNM). SIX2, SIX3, and SIX4 were correlated with higher TNM stages...
  33. Yariz K, Sakalar Y, Jin X, Hertz J, Sener E, Akay H, et al. A homozygous SIX6 mutation is associated with optic disc anomalies and macular atrophy and reduces retinal ganglion cell differentiation. Clin Genet. 2015;87:192-5 pubmed publisher
  34. Carnes M, Liu Y, Allingham R, Whigham B, Havens S, Garrett M, et al. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma. PLoS Genet. 2014;10:e1004372 pubmed publisher
    ..Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR)?=?1.32, p?=?3.87×10(-11))...
  35. Zhang X, Li S, Xiao X, Jia X, Wang P, Shen H, et al. Mutational screening of 10 genes in Chinese patients with microphthalmia and/or coloboma. Mol Vis. 2009;15:2911-8 pubmed
    ..To screen ten genes for mutations in 32 Chinese patients with microphthalmia and/or coloboma...
  36. L pez R os J, Tessmar K, Loosli F, Wittbrodt J, Bovolenta P. Six3 and Six6 activity is modulated by members of the groucho family. Development. 2003;130:185-95 pubmed
    Six3 and Six6 are two genes required for the specification and proliferation of the eye field in vertebrate embryos, suggesting that they might be the functional counterparts of the Drosophila gene sine oculis (so)...
  37. Shiga Y, Nishiguchi K, Kawai Y, Kojima K, Sato K, Fujita K, et al. Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7. PLoS ONE. 2017;12:e0186678 pubmed publisher
    ..00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected...
  38. Forconi F, Sahota S, Raspadori D, Mockridge C, Lauria F, Stevenson F. Tumor cells of hairy cell leukemia express multiple clonally related immunoglobulin isotypes via RNA splicing. Blood. 2001;98:1174-81 pubmed
    ..These HCs appear to be arrested at the point of isotype switch, where RNA processing may precede deletional recombination. (Blood. 2001;98:1174-1181)..
  39. Skowronska Krawczyk D, Zhao L, Zhu J, Weinreb R, Cao G, Luo J, et al. P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma. Mol Cell. 2015;59:931-40 pubmed publisher
    ..Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent ..
  40. Berdasco M, Gomez A, Rubio M, Catala Mora J, Zanon Moreno V, Lopez M, et al. DNA Methylomes Reveal Biological Networks Involved in Human Eye Development, Functions and Associated Disorders. Sci Rep. 2017;7:11762 pubmed publisher
    ..e., PAX6, RAX, SIX6) in a tissue-dependent manner...
  41. Van Dam P, Fokkens L, Ayukawa Y, van der Gragt M, Ter Horst A, Brankovics B, et al. A mobile pathogenicity chromosome in Fusarium oxysporum for infection of multiple cucurbit species. Sci Rep. 2017;7:9042 pubmed publisher
    ..A central part of this chromosome contains all identified candidate effector genes, including homologs of SIX6, SIX9, SIX11 and SIX 13. We show that SIX6 contributes to virulence of Forc...
  42. Gharahkhani P, Burdon K, Fogarty R, Sharma S, Hewitt A, Martin S, et al. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet. 2014;46:1120-1125 pubmed publisher
    ..31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells. ..
  43. Cheng C, Allingham R, Aung T, Tham Y, Hauser M, Vithana E, et al. Association of common SIX6 polymorphisms with peripapillary retinal nerve fiber layer thickness: the Singapore Chinese Eye Study. Invest Ophthalmol Vis Sci. 2014;56:478-83 pubmed publisher
    Recently the common SIX6 missense variant rs33912345 was found to be highly associated with glaucoma...
  44. Philomenadin F, Asokan R, N V, George R, Lingam V, Sarangapani S. Genetic association of SNPs near ATOH7, CARD10, CDKN2B, CDC7 and SIX1/SIX6 with the endophenotypes of primary open angle glaucoma in Indian population. PLoS ONE. 2015;10:e0119703 pubmed publisher
    ..The current study attempts to explore the association of variations near/in genes like ATOH7, SIX1/SIX6 complex, CDKN2B, CARD10, and CDC7 with POAG and its QTs including vertical cup to disc ratio (VCDR), central ..