The vast complexity of primary open angle glaucoma: Disease genes, risks, molecular mechanisms and pathobiology
Introduction
Primary open angle glaucoma (POAG) is an insidious, sight-threatening neurodegenerative disease of the optic nerve, which affects a large proportion of the (elderly) population. Despite tremendous research efforts, the etiology of POAG remains obscure – probably due to the heterogeneous and complex nature of the disease – both on a clinical and on a molecular level.
In the past decade, much effort has gone into elucidating the genetic causes and risk factors of POAG. Application of advanced genetic technology, such as Genome-Wide Association Studies (GWAS), large-scale gene expression studies and proteomics, has yielded a wealth of information. A vast amount of new (candidate) POAG disease genes has been identified, and insights into the molecular mechanisms underlying POAG are increasing. One obvious next step is to attempt to understand the function of these genes and how they act in the pathobiology of POAG. In our lab, and in collaboration with the Rotterdam Study, we recently identified new candidate POAG genes (CDKN2B, ATOH7, SIX1), borderline CDCD7/TGFBR3 and SALL1 (Ramdas et al., 2010, Ramdas et al., 2011a); GAS7 and TMCO1 (van Koolwijk et al., 2012) and we investigated the gene expression levels in POAG-related tissues, such as ciliary body epithelia (Janssen et al., 2012).
In this review, we discuss a variety of aspects of the genetics and the molecular mechanisms underlying POAG and we postulate a model of the pathobiological events that lead to the disease. We discuss the different tissues involved in POAG, their pathobiological changes and their possible role in the disease. Then, we review all the (candidate) POAG loci and genes currently known, and select scientifically confirmed entries. We then review our own and the literature's gene expression data and we determine if, and to what extent, the (selected candidate) POAG genes are expressed in the POAG relevant tissues. Subsequently, for a better understanding of the kind of pathways the POAG genes are involved in, we functionally annotate these (candidate) POAG genes. Finally, in order to gain an insight into the potential role of the disease genes in POAG, and to facilitate future investigations, we review the currently available transgenic mouse models related to the (candidate) POAG genes that developed features of glaucoma.
Section snippets
Primary open angle glaucoma (POAG)
POAG is a progressive optic neuropathy with characteristic changes to the optic nerve head and corresponding visual field defects that are not explained by other diseases (as opposed to secondary glaucomas), together with a normal open anterior chamber (as opposed to angle closure glaucoma) (Casson et al., 2012, Gupta and Weinreb, 1997, Quigley, 2005, Shields and Spaeth, 2012). POAG usually has an onset in adulthood (as opposed to congenital and juvenile glaucoma). From a pathobiological point
Cornea
The cornea, particularly in terms of its thickness and firmness, plays an important role in (the diagnosis of) glaucoma. Several studies have measured central corneal thickness (CCT) and determined the “normal” CCT in a population (Shah et al., 1999, Suzuki et al., 2005, Wolfs et al., 1997). In a meta-analysis of Doughty and Zaman (2000) an average normal CCT of 473–597 μm (95% CI, 474–596) was found. Aging may cause a decline in CCT (Brandt et al., 2008, Cho and Lam, 1999, Foster et al., 1998)
Model of pathobiological changes and disbalances leading to POAG: A hypothesis
POAG is a multifactorial disease in which various tissues and mechanisms are involved. Based on the histopathological and molecular changes in the tissues involved in POAG described in the previous section (Section 3) we built a hypothetical model of POAG (Fig. 6). It is not known where the sequence of events leading to POAG starts. The disease may even have multiple starting points, each setting in motion a chain of events that, in itself or through interaction downstream, contribute to the
Familial linkage studies: genetic loci and causative POAG disease genes
POAG is a genetically complex trait, which occurs both sporadically and in families. POAG disease genes segregating in families can be found using linkage analysis. This usually results in the positional identification of a linked chromosomal region and, subsequently, of the causative POAG disease gene. So far, genetic linkage analysis yielded twenty defined chromosomal regions that are linked to POAG (Table 1). In five genomic loci, the POAG disease genes were actually identified using
Systematic evaluation of expression of 65 POAG disease genes in POAG relevant tissues
We recently published our expression data of the CB neuro-epithelia (Janssen et al., 2012) and became aware that many POAG disease genes are apparently expressed in multiple glaucoma-related tissues. In this section, we will now turn to a systematic evaluation of the expression data of the 65 candidate POAG genes in tissues relevant for POAG. The tissues examined included human cornea (GSE5543; Turner et al., 2007), human CB epithelia (we took the average mean expression values of NPE and PE; GSE37957
Existing animal models of the selected 65 (candidate) POAG disease genes
For the 65 (candidate) POAG disease genes, we searched Pubmed for transgenic animal models (search term “gene name, animal, eye”), and selected those studies that included investigation of the eye and phenotypes of POAG. We identified genetically modified animal models in the literature with mutations in Myoc, Optn, Wdr36, Cyp1b1, Apoe, Atoh, Cav1, Col5a1, Col8a2, Opa1, Pax6 and Tlr4 (Table 6) and discuss them briefly below. It should be noted that animal models exist for most of the other
Summary, conclusions and unresolved issues
While many questions remain unanswered, tremendous progress has been made over the last decade towards the unraveling of the complex pathology of POAG. Family, case-control and genome-wide association studies have revealed multiple (environmental) risk factors and genes that are involved in POAG. We selected and reviewed 65 (candidate) POAG disease genes from the literature on the basis of POAG family or population studies and reviewed their expression in POAG-relevant tissues and their
Acknowledgments
This study was supported by grants from the General Dutch Foundation Preventing Blindness, the National Foundation for Blinds and Low Vision, the Foundation Blinden-Penning, the Foundation Glaucoomfonds, the Rotterdam Foundation of Blinds and the Professor Mulder Foundation (all coordinated by UitZicht, project # UitZicht2008-7). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
We thank Mrs. W. Verweij from the
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Percentage of work contributed by each author in the production of the manuscript is as follows: Sarah F. Janssen, 32.5%; Theo G.M.F. Gorgels, 9%; Wishal D. Ramdas, 7%; Caroline C.W. Klaver, 5%; Cornelia M. van Duijn, 5%; Nomdo M. Jansonius, 9%; Arthur A.B. Bergen, 32.5%.