Leber congenital amaurosis: Genes, proteins and disease mechanisms
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 approximately 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 approximately 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.
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Macroscopic appearances of the retina in the early stage of the disease typically do not reveal anatomic abnormalities.
“Macroscopic appearances of the retina in the early stage of the disease typically do not reveal anatomic abnormalities [129].”
From Molecular Basis for Vitamin A Uptake and Storage in Vertebrates (2016) · cites this paper as [129]
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Self-citation
- Authors
- den Hollander, A. I., Roepman, R., Koenekoop, R. K., & Cremers, F. P. M.
- Affiliations
- Radboud University Nijmegen (NL)
- McGill University Health Centre (CA)
- Corresponding author
- Koenekoop, Robert K.
- Cremers, Frans P.M.
- Venue
- Progress in Retinal and Eye Research
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 27
- Issue
- 4
- Pages
- 391-419
- ISSN
- 1350-9462 (ISSN-L)
- OpenAlex
- W1995140705
- Cited by
- 811
- References
- 9
- Citations by year
- 2026: 17 · 2025: 42 · 2024: 36 · 2023: 32 · 2022: 54 · 2021: 67 · 2020: 44 · 2019: 46 · 2018: 40 · 2017: 53 · 2016: 44 · 2015: 42 · 2014: 48 · 2013: 51 · 2012: 52
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Progress in Retinal and Eye Research (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Leber congenital amaurosis, retinal degeneration, CEP290, GUCY2D, CRB1, RPE65, phototransduction, gene therapy, adeno-associated virus, lentivirus, amblyopia, retinal dystrophy, genetic heterogeneity, disease mechanisms, animal models
- MeSH terms
- Animals, Blindness, Disease Models, Animal, Eye Proteins, Genes, Humans, Retinal Degeneration, Vision, Ocular
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