Leber congenital amaurosis: Genes, proteins and disease mechanisms
Introduction
Inherited sensory diseases are characterized by immense genetic and clinical heterogeneity, which poses great challenges for gene identification, mutation analysis, genetic counselling, and the development of therapies. The most severe form of inherited retinal blindness is Leber congenital amaurosis (LCA), which in most cases is inherited in an autosomal recessive (ar) manner. Research into the molecular causes of LCA in the past 12 years has revealed the underlying disease genes in ∼70% of the cases. Fourteen genes involved in LCA and/or early onset retinal degeneration have been identified encoding proteins important in a wide variety of retinal developmental and physiological pathways. The LRAT, MERTK, RPE65 and TULP1 genes have been implicated in patients with early onset retinal degeneration partially overlapping LCA.
LCA serves as a model for all retinal dystrophies as recently therapeutic gene replacement trials with human subjects have commenced which represent the first attempts to treat inherited blindness. The purpose of this review is to summarize recent developments in our understanding of this devastating disease at the clinical, molecular genetic, cellular, and protein level.
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Clinical characteristics
LCA represents a group of hereditary retinal diseases characterized and unified by the following constellation of four clinical features: severe and early visual loss, sensory nystagmus, amaurotic pupils, and absent electrical signals on electroretinogram (ERG) (Leber, 1869; Franceschetti and Dieterle, 1954). LCA presents very early in life, usually at around the age of 6 weeks, when parents note the oscillations of the eyes (nystagmus) or the absence of fixation. LCA is a rare retinal
Gene-identification strategies
LCA is a heterogeneous disease, caused by mutations in 14 identified genes and an unknown number yet to be discovered genes. The 14 LCA genes have been identified by various methods, including classical linkage analysis, identity-by-descent mapping, and the candidate gene approach. Linkage analysis with microsatellite markers has been a laborious gene-identification method in the past. The availability of single nucleotide polymorphism (SNP) microarrays now enables rapid and relatively cheap
AIPL1
The aryl hydrocarbon receptor protein-like 1 (AIPL1) is a 384-aa protein that shares 49% identity with the human aryl hydrocarbon receptor interacting protein (AIP). A tetratricopeptide repeat (TPR) domain comprising three TRP motifs is conserved in AIP and AIPL1 (Fig. 4). The TPR motif is a degenerate, 34-residue sequence comprising a pair of anti-parallel α-helices. TPR domains function as molecular scaffolds mediating protein interactions. A primate-specific poly-proline-rich sequence of 56
Mouse models for LCA
In Table 2, we summarize 13 mouse models with a retinal dystrophy that to varying degrees mimic human LCA. We have indicated which exons were naturally mutated or targeted by homologous recombination, the methodology used, the ages at which rods and cones start to degenerate, whether light damage plays a role in the retinal dystrophy, other morphological retinal features, and whether the mouse model recapitulates human LCA. All human LCA genes have orthologues in mouse. Four mouse LCA genes (
Therapeutics for LCA
Because the eye is a relatively unique and sophisticated central nervous system appendage, it provides several distinct advantages for gene replacement. Unlike the brain and brainstem, the eye is easily accessible, and harbors a natural subretinal space, where the bolus of therapeutic solution can be placed relatively safely and without leakage into the systemic circulation. This space is also protected from surveillance mechanisms that normally counteract foreign substances. Finally, the eye
Future perspectives
The two ultimate goals of LCA research are to provide efficient and affordable molecular diagnostics and to design novel treatment regimes. To accomplish these goals, a multidisciplinary effort is required combining the strengths of genetics, molecular biology, proteomics, and ophthalmology.
To identify the remaining 30% of genetic causes of LCA, IBD mapping in both consanguineous and outbred families must be expanded by combining high-density SNP data obtained in very large LCA patient cohorts.
Acknowledgments
The LCA research of the authors is supported by grants from The Netherlands Organisation for Scientific Research (VENI 916.56.160 to A.I.d.H., VIDI 917.86.396 to R.R.), the Foundation Fighting Blindness Canada (to R.K.K and F.P.M.C.), the Foundation Fighting Blindness USA (BR-GE-0606-0349-RAD to A.I.d.H.), the EU (Evi-Genoret LSHG-CT-2003-505520 to R.R. and F.P.M.C.), the Fonds de la Recherche en Santé Québec, TD Financial Group, the Grousbeck Foundation; the Edel and Krieble Funds, the Ort
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