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Editors Selection IGR 21-4
Basic Science: Gene studies
Comment by Janey Wiggs on:
50900 Association of genetic variants in the TMCO1 gene with clinical parameters related to glaucoma and characterization of the protein in the eye, Sharma S; Burdon KP; Chidlow G et al., Investigative Ophthalmology and Visual Science, 2012; 53: 4917-4925
Genes contributing to glaucoma may influence intraocular pressure elevation and/or susceptibility of the optic nerve to degeneration. To date, five genes/genomic regions have been statistically associated with primary open-angle glaucoma (POAG): the CAV1/ CAV2 genomic region on chromosome 7, CDKN2BAS, the SIX1/ SIX6 genomic region on chromosome 14, TMCO1, and a regulatory region on chromosome 8q22. While all of these regions were initially identified as associated with POAG or normal-tension glaucoma (NTG), several of them have been further associated with specific features of the disease; for example CDKN2BAS, SIX1/SIX6 and the 8q22 region all appear to impact optic nerve susceptibility to degeneration. In this paper by Sharma et al., evidence is provided to suggest that TMCO1 risk alleles modify the age of disease onset and that this may occur because TMCO1 risk allele carriers have higher IOP. TMCO1 was initially identified as a glaucoma susceptibility gene in a genome-wide association study using 590 severely affected POAG patients and 3,956 controls.1 Subsequently, a genome-wide association study found that TMCO1 was statistically associated with IOP.2 Ocular expression studies included in the Sharma et al., study demonstrate TMCO1 expression in the retina, optic nerve, lamina cribrosa, ciliary body and trabecular meshwork, suggesting that the protein may have roles in both regulation of IOP and in susceptibility to optic nerve disease in glaucoma. Interestingly, TMCO1 loss of function mutations cause an autosomal-recessive syndrome which includes mental retardation, dysmorphism, skeletal and neurological findings, suggesting a role for the protein in cortical development and other developmental processes.3 The function of the protein product of TMCO1 is unknown. Some studies suggest that the protein may co-localize with endoplasmic reticulum while others suggest the protein is associated with mitochondria.4 Further investigations defining the role of TMCO1 in regulation of IOP and/ or age of onset of glaucoma will be of great interest.
References
- Burdon KP, Macgregor S, Hewitt AW, Sharma S, Chidlow G, Mills RA, Danoy P, Casson R, Viswanathan AC, Liu JZ, Landers J, Henders AK, Wood J, Souzeau E, Crawford A, Leo P, Wang JJ, Rochtchina E, Nyholt DR, Martin NG, Montgomery GW, Mitchell P, Brown MA, Mackey DA, Craig JE. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 2011; 43(6): 574-578.
- van Koolwijk LM, Ramdas WD, Ikram MK et al. Common genetic determinants of intraocular pressure and primary open-angle glaucoma. PLoS Genet 2012; 8(5):e1002611.
- Caglayan A, Per H, Akgumus G, Gumus H, Baranoski J, Canpolat M, Calik M, Yikilmaz A, Bilguvar K, Kumandas S, Gunel M. Whole-exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum. Clin Genet 2013; doi: 10.1111/cge.12088.
- Xin B, Puffenberger EG, Turben S, Tan H, Zhou A, Wang H. Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation. Proc Natl Acad Sci U S A 2010; 107(1): 258-263.
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