Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye.
OBJECTIVE
Glaucoma is the leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the most common subtype. We recently reported association of genetic variants at chromosomal loci, 1q24 and 9p21, with POAG. In this study, we determined association of the most significantly associated single nucleotide polymorphism (SNP) rs4656461, at 1q24 near the TMCO1 gene, with the clinical parameters related to glaucoma risk and diagnosis, and determined ocular expression and subcellular localization of the human TMCO1 protein to understand the mechanism of its involvement in POAG.


METHODS
Association of SNP rs4656461 with five clinical parameters was assessed in 1420 POAG cases using linear regression. The TMCO1 gene was screened for mutations in 95 cases with a strong family history and advanced disease. Ocular expression and subcellular localization of the TMCO1 protein were determined by immunolabeling and as GFP-fusion.


RESULTS
The data suggest that individuals homozygous for the rs4656461 risk allele (GG) are 4 to 5 years younger at diagnosis than noncarriers of this allele. Our data demonstrate expression of the TMCO1 protein in most tissues in the human eye, including the trabecular meshwork and retina. However, the subcellular localization differs from that reported in other studies. We demonstrate that the endogenous protein localizes to the cytoplasm and nucleus in vivo and ex vivo. In the nucleus, the protein localizes to the nucleoli.


CONCLUSIONS
This study shows a relationship between genetic variation in and around TMCO1 with age at diagnosis of POAG and provides clues to the potential cellular function/s of this gene.
Department of Ophthalmology, Flinders University, GPO Box 2100, Adelaide 5001, Australia. shiwani.sharma@flinders.edu.au
Shiwani
S
Sharma
Kathryn P
KP
Burdon
Glyn
G
Chidlow
Sonja
S
Klebe
April
A
Crawford
David P
DP
Dimasi
Alpana
A
Dave
Sarah
S
Martin
Shahrbanou
S
Javadiyan
John P M
JP
Wood
Robert
R
Casson
Patrick
P
Danoy
Kim
K
Griggs
Alex W
AW
Hewitt
John
J
Landers
Paul
P
Mitchell
David A
DA
Mackey
Jamie E
JE
Craig
D000367:Age Factors; D017668:Age of Onset; D000483:Alleles; D015220:Calcium Channels; D005260:Female; D020022:Genetic Predisposition to Disease; D005902:Glaucoma, Open-Angle / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D012307:Risk Factors; D014129:Trabecular Meshwork / Q000378:metabolism
D015220:Calcium Channels; D008565:Membrane Proteins; C575495:TMCO1 protein, human