Mutations In Lca9 Cause Human Congenital Blindness Due To Leber Congenital Amaurosis

Abstract

Purpose: : Leber Congenital Amaurosis (LCA) represents the most severe form of human inherited retinal dystrophies with photoreceptor neuron degeneration and blindness with an incidence of ~1 in 80,000. Genetically and clinically heterogeneous, 16 mutant genes are thus far implicated in LCA, explaining 70% of patients, while their encoded proteins range in function from ciliary transport to photoreceptor development. The goal of our studies are to identify novelLCA disease genes underlying the 30% of unsettled LCA patients, which is likely to provide important insights of the mechanisms of the disease.

Methods: : A whole exome sequencing approach was used to sequence a collection of 50 LCA patients. Candidate genes identified were then further confirmed by disease segregation, additional patient cohort screen, comparing to matching controls, and functional studies.

Results: : Using exome sequencing, we identified mutations in LCA9 in 7 families with LCA. Interestingly, in addition to the typical LCA phenotypes, all patients shared macular colobomas, a developmental abnormality with an absent fovea (a metabolically active tissue) and neurons, suggesting that LCA9 may be involved in early foveal and retinal development. Follow up functional assays of the mutations identified in our study indicated that these mutations impair the enzymatic activity and/or destabilize the protein. In situ mutagenesis experiments of selected LCA9 mutations found in our patients revealed abnormal protein expression.

Conclusions: : We have identified LCA9 as a novel LCA disease gene. LCA9 maps to 1p36 and patients with LCA9 mutations share a similar phenotype with the original LCA9 locus patients in the original linkage study by Keen et al, 2011 in a large Pakistani family. Our findings not only provide insights into a new disease mechanism for LCA but also establish the first link between LCA9 and a human nervous system disease.

Keywords: photoreceptors • candidate gene analysis • mutations