Leber congenital amaurosis (LCA) is a severe form of congenital blindness due to inherited recessive traits. As such it is typically caused by the inheritance of two copies of a mutated gene, one from each parent. The parents are heterozygous and clinically unaffected by the disease.
There are about 22 genes currently identified as associated with LCA and more are being discovered. Those now known are found in about half of the total cases of LCA, which means no genetic cause can be attributed to the others. For this reason, research is going on to detect all the genes that can cause this type of syndrome, using genotyping techniques such as DNA microarrays or next generation sequencing as well as older methods that include linkage analysis and candidate gene identification.
The genes that are confirmed to be connected to the etiology of LCA include AIPL1, GUCY2D, and RDH12, all of which were detected using linkage analysis.
In some patients, the change in retinal expression suggests the mutations responsible, which narrows down the tests required and the number of genes to be analyzed. This makes genetic testing more cost-effective. This recognition of retinal genotype-phenotype association led to the discovery of mutations in RPE65 or LCA2, LRAT, CRB1 and RPGRIP1. Lately, however, mutations that have already been discovered are being identified in LCA using DNA microarrays which is a cheaper, quicker and more comprehensive screening technique. On the other hand, it will not pick up unidentified mutations. Overall, the identification of mutations is successful in about 60% of LCA patients. A variant of this technique called homozygosity mapping is used to detect homozygous mutations only, and has brought forth mutations in CEP290, SPATA, and LCA5, among others. Finally, homozygosity mapping and exome sequencing has led to the discovery of mutations such as those in KCNJ1, CNGA3 and BBS4.
Some of the common defects identified are discussed below.
This gene is also called LCA1 and it encodes retinal photoreceptor-specific guanylyl cyclase. This enzyme is necessary in helping the light receptor to recover to the dark stage following light excitation by resynthesizing cyclic guanylate monophosphate (cGMP). The loss of this protein may cause about a fifth of all LCA cases. Clinically, these children have very poor vision from birth onwards, which is non-progressive and is associated with lack of response to visual stimuli, photophobia, hyperopia and nystagmus. The electroretinogram (ERG) is undistinguishable.
RPE65 or LCA2
This protein is found in the retinal pigment epithelium, the nutritive and supportive layer of the retina adjacent to the photoreceptors. It plays a crucial part in the regeneration of the visual pigment following its light-induced breakdown. Such patients lose a significant number of cone cells early, and they account for about 16% of cases. They have early and severe visual loss, nystagmus and night blindness.
This coding region houses many mutations that can cause not only LCA but also retinitis pigmentosa, because of different degrees of loss of function with each mutation. Early truncations are associated with LCA because of severe loss of function. Even a mutation in the non-coding or intron sequence associated with this region may lead to loss of function as a result of aberrant splicing of the transcript, and cause disease.
AIPL1 or LCA4
This protein is the aryl hydrocarbon receptor protein-like 1 and is required for phosphodiesterase activity in the rod cells. Missense and stop mutations in this area cause up to 10% of LCA cases. The patients suffer severe and early visual loss with maculopathy and pigment abnormalities. Other mutations of this coding area may cause various syndromes associated with blindness.
The presence of null mutations in the retinitis pigmentosa GTPase regulator interacting protein 1 gene or LCA6 gene causes 5% of LCA. This protein plays a vital role in the cilia connecting the photoreceptors and its loss leads to degeneration of the outer segments of the photoreceptors, which are responsible for sensing light. This means patients lose visual responses very early, while still retaining their light receptors for many years.
This gene encodes the protein crumbs homolog 1, which is found in the retina and in the brain. It is crucial to proper maintenance of cell polarity in embryonic life that is responsible for the correct development of the epithelial tissues. Lack of this protein causes thickening and poorly stratified retinal layers, and mutations here cause not only LCA but also other diseases including retinitis pigmentosa.
Many other genes may cause the development of LCA, including the CEP290 or LCA10 regions which encodes a centrosomal protein in the photoreceptor connecting cilia, and RDH12 or LCA13 which encodes retinal dehydrogenase responsible for switching of trans-cis retinols. All known mutations affect the normal development and functioning of the retina. Genetic diversity is the hallmark of LCA and much more remains to be discovered about the causes of this syndrome.