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Association of Genetic Variants in the TMCO1 Gene with Clinical Parameters Related to Glaucoma and Characterization of the Protein in the Eye

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Association of Genetic Variants in the TMCO1 Gene with Clinical Parameters Related to Glaucoma and Characterization of the Protein in the Eye Glaucoma Association of Genetic Variants in the TMCO1 Gene with Clinical Parameters Related to Glaucoma and Characterization of the Protein in the Eye Shiwani Sharma,1,9 Kathryn P. Burdon,1,9 Glyn Chidlow,2 Sonja Klebe,1,3 April Crawford,1 David P. Dimasi,1 Alpana Dave,1 Sarah Martin,1 Shahrbanou Javadiyan,1 John P. M. Wood,2 Robert Casson,2 Patrick Danoy,4 Kim Griggs,3 Alex W. Hewitt,5 John Landers,1 Paul Mitchell,6 David A. Mackey,5,7,8 and Jamie E. Craig1 PURPOSE. Glaucoma is the leading cause of irreversible RESULTS. The data suggest that individuals homozygous for the blindness worldwide. Primary open angle glaucoma (POAG) rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis is the most common subtype. We recently reported association than noncarriers of this allele. Our data demonstrate expres- of genetic variants at chromosomal loci, 1q24 and 9p21, with sion of the TMCO1 protein in most tissues in the human eye, POAG. In this study, we determined association of the most including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other significantly associated single nucleotide polymorphism (SNP) studies. We demonstrate that the endogenous protein localizes rs4656461, at 1q24 near the TMCO1 gene, with the clinical to the cytoplasm and nucleus in vivo and ex vivo. In the parameters related to glaucoma risk and diagnosis, and nucleus, the protein localizes to the nucleoli. determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its CONCLUSIONS. This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG involvement in POAG. and provides clues to the potential cellular function/s of this METHODS. Association of SNP rs4656461 with five clinical gene. (Invest Ophthalmol Vis Sci. 2012;53:4917–4925) DOI: parameters was assessed in 1420 POAG cases using linear 10.1167/iovs.11-9047 regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular laucoma refers to a group of neurodegenerative ocular expression and subcellular localization of the TMCO1 protein Gdiseases united by a clinically characteristic optic neurop- were determined by immunolabeling and as GFP-fusion. athy. Open-angle glaucoma (OAG) is common, with a prevalence of approximately 3% in people older than 50 years.1 The disease has long been known to have a genetic From the Departments of 1Ophthalmology and 3Pathology, component. First-degree relatives of affected patients exhibit a Flinders University, Flinders Medical Centre, Adelaide, Australia; 9-fold increased relative risk of developing primary OAG 2South Australian Institute of Ophthalmology, Hanson Institute & (POAG) compared with the general population.2 The Glauco- 4 The University of Adelaide, Adelaide, Australia; The University of ma Inheritance Study in Tasmania (GIST) revealed that a Queensland Diamantina Institute, Princess Alexandra Hospital, 5 positive family history is found in approximately 60% of cases Brisbane, Australia; Centre for Eye Research Australia, University 3 of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, of POAG when family members are examined, and the disease Australia; 6Centre for Vision Research, Department of Ophthalmol- is more severe in people with a family history of glaucoma, ogy and Westmead Millennium Institute, University of Sydney, compared with those with ‘‘sporadic’’ glaucoma.4 Mutations in Westmead, Australia; 7Lions Eye Institute, University of Western the myocilin gene (MYOC) are the most common reported Australia, Centre for Ophthalmology and Visual Science, Perth, genetic cause of POAG and account for approximately 3% to Australia; and 8Discipline of Medicine, University of Tasmania, 5% of cases.5 Mutations in optineurin (OPTN) and WDR36 Hobart, Australia. genes have also been implicated.5 Recent genome-wide 9 These authors contributed equally to the work presented here association studies have identified common variants at several and should therefore be regarded as equivalent authors. new genetic loci are associated with POAG, including CAV1 Supported by National Health and Medical Research Council and CAV2 on chromosome 7q31; CDKN2B-AS1, CDKN2A, and (NHMRC) of Australia, Glaucoma Australia, and Ophthalmic Re- 6,7 search Institute of Australia. Support was also provided by the CDKN2B on 9p21; and TMCO1 on 1q24. The mechanism of NHMRC Career Development Award (KPB) and the Practitioner disease association is not yet clear for any of these genetic Fellowship (JEC). associations and very little is known about the normal function Submitted for publication November 9, 2011; revised March 27 of TMCO1 and its role in the eye. and May 27, 2012; accepted June 12, 2012. The TMCO1 gene encodes the Transmembrane and coiled- Disclosure: S. Sharma,None;K.P. Burdon,None;G. coil domains-1 protein which belongs to the DUF841 Chidlow,None;S. Klebe,None;A. Crawford,None;D.P. Dimasi, superfamily of unknown function.8 Thegeneislocated None; A. Dave,None;S. Martin,None;S. Javadiyan,None;J.P.M. approximately 6 Mb upstream of the known POAG gene Wood,None;R. Casson,None;P. Danoy,None;K. Griggs,None; MYOC on chromosome 1. The protein sequence is highly A.W. Hewitt,None;J. Landers,None;P. Mitchell,None;D.A. 9 Mackey,None;J.E. Craig,None conserved across mammalian species. The gene is expressed 9 Corresponding author: Shiwani Sharma, Department of Oph- in a variety of human adult and fetal tissues at varying levels, thalmology, Flinders University, GPO Box 2100, Adelaide 5001, including ocular tissues.6 Immunohistochemistry revealed Australia; shiwani.sharma@flinders.edu.au. cytoplasmic labeling in the rat retinal ganglion cell layer.6 Investigative Ophthalmology & Visual Science, July 2012, Vol. 53, No. 8 Copyright 2012 The Association for Research in Vision and Ophthalmology, Inc. 4917 Downloaded From: http://iovs.arvojournals.org/pdfaccess.ashx?url=/data/journals/iovs/933262/ on 02/09/2017 4918 Sharma et al. IOVS, July 2012, Vol. 53, No. 8 The green fluorescent protein (GFP)-fusion of TMCO1 has provided written informed consent. Approval was obtained from the been reported to localize to endoplasmic reticulum and Golgi Human Research Ethics Committees (HRECs) of Southern Adelaide apparatus in COS7 cells,10 and to the mitochondria in porcine Health Service/Flinders University, University of Tasmania, and The PK-15 cells.8 These reports suggest that the subcellular Royal Victorian Eye and Ear Hospital. All participants were screened for localization of the protein may differ depending on cell type. mutations in the MYOC gene by direct sequencing of exon 3 on an ABI A homozygous frame-shift mutation in the TMCO1 gene has PRISM 3100 Genetic Analyzer (Applied Biosystems, Foster City, CA) been shown to cause a rare recessive syndrome in the Amish, with BigDye Terminators (Applied Biosystems) according to standard consisting of craniofacial dysmorphism, skeletal anomalies, and protocols. Primer sequences are available on request. mental retardation, now known as ‘‘TMCO1 defect syn- drome.’’9 There are no reports of glaucoma in this family. Genotyping and Association Analysis Our recent study failed to find any coding mutations in POAG patients carrying two risk haplotypes at the TMCO1 locus, Genotyping of the rs4656461 SNP was conducted as previously indicating that coding mutations in TMCO1 are unlikely to reported.6 Briefly, samples originally included in the discovery phase of account for the association observed with POAG.6 the genome-wide association scan were genotyped on Omni1 SNP The most associated single nucleotide polymorphism (SNP) arrays (Illumina Inc., San Diego, CA), whereas those included in the at the 1q24 locus (rs4656461) is just 30 to TMCO1 and the replication phase were typed with iPlex Gold chemistry on an Autoflex second ranked SNP rs7518099 is within intron 2 of this gene and Mass Spectrometer (Sequenom Inc., San Diego, CA). Each clinical trait is in almost complete linkage disequilibrium with rs4656461. In was assessed for association with SNP rs4656461 (the glaucoma- addition, the highest ranked imputed SNP, rs7524755 is within associated SNP tagging the at-risk haplotype as reported previously6) the 30 UTR of TMCO1.6 All the associated SNPs are within the using linear regression under a dominant genetic model. This model same linkage disequilibrium block as TMCO1 with no other was chosen to maintain statistical power because this SNP is relatively transcripts in the block. The common haplotype across the rare (minor allele frequency approximately 12%) and only 24 gene, which is efficiently tagged by the most associated SNP, homozygous patients were observed in our cohort. SNP genotypes increases the risk of POAG. This association was discovered in a were coded as carriers of the POAG risk allele (GA or GG genotype) cohort of POAG patients with severe blinding disease, and noncarriers (AA genotype), and analyzed in the model as a replicated in a second similar cohort and another cohort with categorical variable. The assumptions of linear regression were met. A less-severe glaucoma.6 From these data, however, it is as yet P value of 0.01 was required to account for the multiple testing of five unclear whether TMCO1 genetic variation can be used to traits (highest recorded IOP, age at diagnosis, mean deviation, cup:disc pinpoint a distinct subtype of POAG or if TMCO1 mutations ratio, and central corneal thickness). Significantly associated traits were might contribute to some cases of familial OAG. then assessed under multivariate analysis including each of the other In the present study, we further investigated the TMCO1 traits as well as sex in the model. Analyses were conducted including gene for association with clinical traits relevant to glaucoma and excluding patients with known MYOC mutations. All analyses were risk and diagnosis, and screened for mutations in patients with conducted using IBM-SPSS Statistics V19 (IBM Corp., Armonk, NY). a strong family history of POAG.
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