Identifying retinal disease genes: how far have we come, how far do we have to go?

Abstract

One of the great success stories in retinal disease (RD) research in the past decade has been identification of many of the genes and mutations causing inherited retinal degeneration. To date, more than 133 RD genes have been identified, encompassing many disorders such as retinitis pigmentosa, Leber congenital amaurosis, Usher syndrome and macular dystrophy. The most striking outcome of these findings is the exceptional heterogeneity involved: dozens of disease-causing mutations have been detected in most RD genes; mutations in many different genes can cause the same disease; and different mutations in the same gene may cause different diseases. Superimposed on this genetic heterogeneity is substantial clinical variability, even among family members with the same mutation. The RD genes involve many different pathways, and expression ranges from very limited (e.g. expressed in rod photoreceptors only) to ubiquitous. These findings raise several general questions--in addition to the extraordinary number of specific, biological problems revealed. What fraction of the patient population can now be accounted for by the known RD genes? How many more RD genes will be found, and how should we find them? Are we dealing with just a handful of disease mechanisms or are there many different routes to retinal degeneration? How will this extreme heterogeneity affect our ability to diagnose and treat patients? These questions are considered in this summary.