Genetics of Eye Disease
During the past decade, significant advances have been made in our understanding of the genetics of eye diseases in humans. This has been facilitated by the development of advanced molecular biology techniques, increased funding for the study of these diseases, and genome sequencing. The current availability of these tools invites further investigation of underlying gene mutations for many ocular disorders that are presumed to have an inherited basis in the horse. Such investigations have already identified candidate genes for congenital stationary night blindness (CSNB) and multiple congenital ocular anomalies (MCOA) syndrome, and continued analysis will likely soon reveal causative mutations for these phenotypes. The goal of these investigations is to gain an improved understanding of the pathogenesis of such diseases at a subcellular level, enable more accurate diagnosis, and achieve better clinical management. As equine ophthalmologists appreciate the role of genetic factors in an increasing number of ophthalmic disorders of the horse, this field of research will continue to grow.
Genetic Basis of Eye Diseases
Variations in gene expression contribute to the development of many eye diseases. Of these, the inherited genetic eye diseases involve changes in the genome, passed from parent to offspring through the genetic codes for the specific trait. Noninherited genetic factors are new mutations that cause disease or alter disease susceptibility, but do not involve the germline and so are not passed on to future generations. In this chapter attention is focused on heritable genetic eye disease.
Heritable genetic eye diseases may be the result of a single mutated gene that causes a protein product to be missing or altered, with consequent phenotypic changes. Alternatively, inheritance of these diseases may be polygenic, multifactorial in cause, and associated with multiple genes in combination with environmental factors and may hence be variable in expression. However, even inherited single-mutation diseases can result in different phenotypes. These phenotypic differences can be partially explained by the action of gene modifiers and allelic variation, which alter the penetrance and expressivity of a trait. Additionally, a disorder caused by an inherited genetic condition, such as cataract, often has nongenetic causes in other individuals, so the contribution of genetics can easily be overlooked.
To date, a number of eye diseases suspected to be heritable have been described in the horse. However, of these diseases, the mode of inheritance and specific genetic basis for the disease remains unknown in most instances. This contrasts with the situation in other species such as the human and mouse, in which genetic factors have been investigated in detail and many causative gene mutations described. Although our understanding of the genetic basis of eye diseases in the horse is in its infancy, the current availability of powerful molecular tools and the recent sequencing of the equine genome promise much growth in this field.
Investigating Inherited Eye Diseases
The investigation of eye diseases that have a presumed inherited basis should begin with a detailed description of the phenotype. Both affected and unaffected related horses should be examined, and variations in disease severity should be noted. These data can be used to generate a pedigree, ideally spanning at least two generations, for determination of a mode of inheritance. This typically allows identification of a Mendelian inheritance pattern, such as autosomal recessive, or a more complex multifactorial inheritance pattern in which there is interplay between several genetic and environmental factors. Determination of the mode of inheritance will then help in identification of the chromosomal location of the trait through linkage analysis. The process of linkage analysis works by mapping the location of a disease-causing gene using genetic markers that are coinherited with the disease phenotype. Candidate genes in the mapped region can then be investigated by determining whether the gene locus is linked to the disease status, which is achieved by genotyping animals within the pedigree. If the locus if strongly associated with the disease, it is screened for possible disease-causing mutations.
The initial goal of these efforts is often the development of a DNA-based test for the disease. These are preferably polymerase chain reaction–based specific mutation detection tests but can also be linked marker tests. The development of such tests will allow equine ophthalmologists to not only clinically diagnose inherited ocular disorders but also confirm the clinical diagnosis with molecular means. This will help in the provision of specific management advice, more accurate prediction of the clinical course of the disease, and planning of possible emerging therapies.