Inherited Severe Photoreceptor Diseases

The retina represents the visual sensory receptor of the central nervous system (CNS). It is a multi-layer of highly specialized neurons (Figure 1), including photoreceptors that are responsible for conversion of the light stimuli into electric signals (phototransduction) through to the retinal ganglion cells (RGC) and then to the visual cortex. The neural retina is overlaid by the retinal pigment epithelium (RPE, Fig. 1), which takes part in the visual cycle.


© James Crook, April 1998

Figure 1. Schematic representation of the retina.
The photoreceptor cells (rods and cones) are located in the posterior part of the retina next to the choroid. Each bipolar cell receives signals from many photoreceptors and each ganglion cell from many bipolars. Horizontal cells interconnect photoreceptors allowing one group of receptors to influence the signals from another group. Amacrine cells perform a similar function at the bipolar/ganglion interface. The pigment layer contains the retinal pigment epithelial (RPE) cells.

Mutations in many of the genes encoding for proteins involved in phototransduction or the visual cycle cause inherited retinal degeneration. Many blinding disorders, that affect the retina and for which no therapies are currently available, are due to inherited conditions such as Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA), which are both the focus of the AAVEYE consortium. These disorders are highly genetically heterogeneous. Over 140 different loci responsible for RP and 10 for LCA ( have been identified so far. More than 50% of RP and LCA patients are negative when screened for mutations in known RP/LCA genes. The RP and LCA high genetic heterogeneity is responsible for the high costs and efforts required for the molecular diagnosis of affected patients.

Most of the genes responsible for RP and LCA are expressed in photoreceptors exclusively or in addition to other cell types. Mutations in PDE6B and AIPL1 are particularly interesting because: i. they are relatively common causes of severe recessively inherited retinal degeneration (PDE6B causes RP and AIPL1 causes LCA); ii. animal models bearing Pde6b and Aipl1 mutations are available that resemble the disease found in humans, and iii. bPDE and AIPL1 deficiencies share a common pathogenetic mechanism.

PDE6B encodes the β-subunit of the rod-specific phosphodiesterase (bPDE). This protein is an essential element in the phototransduction cascade, where it is responsible for the hydrolysis of cGMP and the subsequent closure of cGMP-gated ion channels. Mutations in the PDE6B gene have long been linked to autosomal recessive Retinitis Pigmentosa as well as autosomal dominant RP [see] (Figure 2).


Figure 2. (A) View through the pupil of a normal eye showing optic nerve, macula, and vascularized retina. (B) View through the pupil of an eye with late-stage retinitis pigmentosa showing pigmentary changes and attenuated vessels, which occur with photoreceptor loss.
[Taken from Smith LEH (2004). Bone marrow-derived stem cells preserve cone vision in retinitis pigmentosa. J Clin Invest 114: 755-757].

Two naturally occurring mouse models of this disease exist, namely rd1 and rd10. Both are due to mutations in the rod-specific Pde6b gene. The rd1 mouse has a nonsense mutation in exon 7 of the gene, resulting in a full knock-out phenotype, characterized by a rapid degeneration of the rod photoreceptor cells from day P8 (post-natal day 8) onwards. At the age of 1 month, only the cone photoreceptors remain in these animals. The second model, the rd10 mouse, has a missense mutation in exon 13 of the Pde6b gene, which results in a slower onset rod degeneration. In these animals the first histological signs of retinal degeneration are apparent after 3 weeks, after which a rapid degeneration leaves only cones at day P45 (Fig. 2).

The AIPL1 gene encodes a photoreceptor cell-specific chaperone that is hypothesized to be responsible for correct folding or localization of the bPDE. Mutations in the AIPL1 gene have been shown to result in Leber Congenital Amaurosis, a form of inherited childhood blindness [see]. The two animal models of disease caused by mutations in the Aipl1 gene are the knockout (Aipl1 -/-) mouse and the hypomorphic mutant (Aipl1 h/h) mouse. The knock-out mouse shows a very rapidly progressing disease with a complete loss of photoreceptors between 4 and 7 weeks, depending on the strain. The hypomorphic mutant has a slow progressing photoreceptor cell degeneration characterized by an onset of degeneration at 3 months; after 8 months approximately half the photoreceptor cells in these animals are lost. In the absence of AIPL1, a lack of functional bPDE results in a disruption of the phototransduction cascade and the subsequent loss of the photoreceptor cells.

Mutations in PDE6B and AIPL1 are therefore common causes of recessive severe photoreceptor degeneration in humans and mice through a common mechanism involving bPDE activity.