Leber congenital amaurosis: Genes, proteins and disease mechanisms

https://doi.org/10.1016/j.preteyeres.2008.05.003Get rights and content

Abstract

Leber congenital amaurosis (LCA) is the most severe retinal dystrophy causing blindness or severe visual impairment before the age of 1 year. Linkage analysis, homozygosity mapping and candidate gene analysis facilitated the identification of 14 genes mutated in patients with LCA and juvenile retinal degeneration, which together explain approximately 70% of the cases. Several of these genes have also been implicated in other non-syndromic or syndromic retinal diseases, such as retinitis pigmentosa and Joubert syndrome, respectively. CEP290 (15%), GUCY2D (12%), and CRB1 (10%) are the most frequently mutated LCA genes; one intronic CEP290 mutation (p.Cys998X) is found in ∼20% of all LCA patients from north-western Europe, although this frequency is lower in other populations. Despite the large degree of genetic and allelic heterogeneity, it is possible to identify the causative mutations in ∼55% of LCA patients by employing a microarray-based, allele-specific primer extension analysis of all known DNA variants.

The LCA genes encode proteins with a wide variety of retinal functions, such as photoreceptor morphogenesis (CRB1, CRX), phototransduction (AIPL1, GUCY2D), vitamin A cycling (LRAT, RDH12, RPE65), guanine synthesis (IMPDH1), and outer segment phagocytosis (MERTK). Recently, several defects were identified that are likely to affect intra-photoreceptor ciliary transport processes (CEP290, LCA5, RPGRIP1, TULP1). As the eye represents an accessible and immune-privileged organ, it appears to be uniquely suitable for human gene replacement therapy. Rodent (Crb1, Lrat, Mertk, Rpe65, Rpgrip1), avian (Gucy2D) and canine (Rpe65) models for LCA and profound visual impairment have been successfully corrected employing adeno-associated virus or lentivirus-based gene therapy. Moreover, phase 1 clinical trials have been carried out in humans with RPE65 deficiencies. Apart from ethical considerations inherently linked to treating children, major obstacles for the treatment of LCA could be the putative developmental deficiencies in the visual cortex in persons blind from birth (amblyopia), the absence of sufficient numbers of viable photoreceptor or RPE cells in LCA patients, and the unknown and possibly toxic effects of overexpression of transduced genes. Future LCA research will focus on the identification of the remaining causal genes, the elucidation of the molecular mechanisms of disease in the retina, and the development of gene therapy approaches for different genetic subtypes of LCA.

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.

Section snippets

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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