Genetics of Leber congenital amaurosis

• Published in: Acta ophthalmologica (Oxford, England) Vol. 89; no. s248
• Main Authors: DEN HOLLANDER, AI, ROEPMAN, R, KOENEKOOP, RK, CREMERS, FPM
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-09-2011; Wiley Subscription Services, Inc
• Subjects: Animal models; Brain; Clinical trials; Congenital defects; Gene mapping; Gene therapy; Guanylate cyclase 1; Leber congenital amaurosis; Linkage analysis; Molecular modelling; Morphogenesis; Mutation; Neurodevelopmental disorders; Photoreceptors; Phototransduction; Retina; Retinitis; Retinitis pigmentosa; Vitamin A
• ISSN: 1755-375X; 1755-3768
• DOI: 10.1111/j.1755-3768.2011.2423.x

Purpose To give an overview of our current knowledge of the genetic causes of Leber congenital amaurosis (LCA).
Methods Current literature on the genetic causes of LCA and the function of the defective gene products will be reviewed. In addition therapeutic options for the various genetic subtypes will be discussed.
Results Linkage analysis, homozygosity mapping and candidate gene analysis facilitated the identification of 15 genes mutated in patients with LCA, 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, GUCY2D and CRB1 are the most frequently mutated LCA genes; one intronic CEP290 mutation (p.Cys998X) is found in 20% of LCA patients from north‐western Europe, although this frequency is lower in other populations. The LCA genes encode proteins with a wide variety of retinal functions, such as photoreceptor morphogenesis, phototransduction, vitamin A cycling and intra‐photoreceptor ciliary transport processes. Rodent, avian and canine models for LCA 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. In addition, a phase 1 clinical trial with a retinoid compound has been initiated in LCA patients with RPE65 and LRAT mutations.
Conclusion 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.