Mortality in primary open-angle glaucoma: 'two cupped discs and a funeral'.

PURPOSE: The aim of this study was to investigate the causes of mortality in individuals with open-angle glaucoma (OAG). METHODS: All-cause mortality data from the Registry of Births, Deaths and Marriages for the Australian state of Tasmania, for all people who were at least 40 years of age at the time of death, were classified using International Classification of Diseases-10 guidelines. This information was cross-referenced to identify participants in the Glaucoma Inheritance Study in Tasmania (GIST) who had died. Contingency tables were used for crude analysis and then models were constructed, adjusting for age at death as well as gender. RESULTS: Between 1996 and 2005, a total of 33 879 deaths were recorded. Data were unavailable for 4868 (14.4%) people. The mean age at death for the study sample was 78.4+/-11.5 (range 41-109) years. Of those cases known to have OAG by their participation in GIST (n=2409), full mortality data were available for 741 (92.0%). Following adjustment for the age at death and male gender, the odds ratio for death due to ischaemic heart disease in people with OAG compared to the general population not known to have OAG was significant (OR=1.30, 95% CI: 1.08-1.56; P=0.006). Crude analysis revealed that there were significantly fewer people with OAG who died due to metastatic cancer (P<0.001); however, this did not remain significant following adjustment for age and gender. CONCLUSION: The pathoaetiological relationship between OAG and ischaemic heart disease is unclear and requires further investigation. Increased awareness of the association between cardiovascular disease and OAG is warranted.

Septamer element-binding proteins in neuronal and glial differentiation.

Differentiation of progenitors into neurons and glia is regulated by interactions between regulatory DNA elements of neuron- and glia-specific genes and transcription factors that are differentially expressed by progenitors at progressive stages of neural development. We have identified a novel DNA regulatory element (TTTGCAT = septamer) present on the enkephalin (ENK), neuronal cell adhesion molecule, neurofilament of 68 kDa (NF68), growth-associated protein of 43 kDa, glial high-affinity glutamine transporter, tyrosine hydroxylase, etc., genes. When septamer function was blocked by introducing septamer competitor DNA into primary differentiating neural cultures, mRNA levels of ENK, NF68, and glial fibrillary acidic protein decreased by 50-80%, whereas no effect was seen using a control DNA. Septamer elements serve as binding sites for lineage-specific multimeric complexes assembled from three distinct nuclear proteins. Progenitors express a 16 kDa protein (p-sept) which binds to DNA as a homodimer (detected as the 32 kDa P-band). Cells that entered the neuronal lineage express an additional 29 kDa protein (n-sept) that binds to the homodimerized p-sept, and together they form a 62 kDa multimer (detected as N-band). Cells that entered the glial lineage express a distinct 23 kDa protein (g-sept), which along with the homodimerized p-sept form a 56 kDa multimer (observed as G-band). The binding of the distinct protein complexes (P, G, and N) to the septamer site causes a lineage-specific DNA bending (P = 53 degrees; G = 72 degrees; and N = 90 degrees ), which may contribute to the regulatory effect of the septamer interaction. In summary, septamer and its binding proteins represent novel protein-DNA interactions that may contribute to the regulation of neuroglial differentiation in the developing mammalian CNS.

Sample and probe: a novel approach for identifying development-specific cis-elements of the enkephalin gene.

We have developed a novel 'sample and probe' approach as a means to identifying specific DNA elements of the enkephalin gene that control differentiation of the enkephalinergic phenotype during neurodevelopment. The approach is a systematic spatiotemporal analysis of protein-DNA interactions; soluble nuclear proteins ('samples') prepared from microdissected regions of the developing brain are 'probed' with radiolabeled DNA fragments representing various regulatory regions of the enkephalin gene. The resulting spatiotemporal 'molecular maps', i.e. characteristic patterns of protein-DNA complexes showed DNA regions that harbor potential cis-elements regulating differentiation of the enkephalin phenotype at various stages of neurodevelopment. DNase I footprint analysis of such a DNA region identified a binding site (GACGGGAGATCGCTCGT) which is similar to the motif for a lymphoid-specific, developmentally regulated transcription factor, Ikaros, suggesting that the developing brain expresses Ikaros-like transcription factor(s) in a spatiotemporally defined manner. In summary, our approach offers a unique view into the chronology of coordinated protein-DNA interactions and will greatly facilitate identifying DNA elements and isolating development-specific transcription factors.

The problem of overlapping glaucoma families in the Glaucoma Inheritance Study in Tasmania (GIST).

The Glaucoma Inheritance Study in Tasmania (GIST) is a population survey of Australia's island state, Tasmania (population 450,000). Its aim is to find families with autosomal dominant, adult-onset, primary open angle glaucoma (POAG) suitable for genetic linkage analysis. POAG is relatively common, affecting around 3% of the Australian population. By finding the large families with POAG and identifying all the descendants in a captive population, it is possible that there may be overlap of different glaucoma pedigrees. Three of the first thirteen families in the study were composed of overlapping pedigrees. In one GIST family, GTas3, there has been intermarriage with other pedigrees with glaucoma on five occasions. The possibility of multiple genotypes was also reinforced by the inability to determine a single glaucoma phenotype in this family. When finding large families of POAG for linkage analysis, researchers must be aware of the risk of affected individuals inheriting their gene from the alternate parent. Thus, the alternate parents or their families must be examined, especially if the phenotype is atypical for the rest of the family.