CPH1, a new gene for Dominant Optic Atrophy

Abstract

Purpose : Hereditary Optic Neuropathies (HON) are genetically heterogeneous diseases. HON can be isolated, affecting exclusively the retinal ganglion cell, or syndromic. HON are linked to genes coding proteins with a major role in the mitochondrial function. Our purpose is to characterize a new gene causing HON, called CPH1.

Methods : Whole-exome sequencing (WES) method was used to characterize the genetic cause of a new form of Dominant Optic Atrophy associated with a maculopathy. Sanger sequencing was used to verify the mutations. Then, we used fibroblasts to characterize mitochondrial dysfunction in patient cells. Zebrafish model were used to in vivo study effect of the mutation on visual function.

Results : WES analysis was performed on several members of a very large family with a dominant optic atrophy (DOA) and a photoreceptor anomaly in the central part of the retina. A dominant mutation was identified in a candidate gene called CPH1. This gene encodes a protein involved in the mitochondrial function. We then screened CPH1 in a large cohort of DOA families and found additional mutations. Our results on patients’ fibroblasts show that CPH1 protein expression is decreased compared to controls, whereas the mRNA level of CPH1 remained unchanged. Interestingly, fibroblasts carrying the mutation show a decrease of mitochondrial respiratory chain and affection in mitochondria with transmission electron microscopy. We used morpholinos and CPH1 RNA mutant to model the disease in zebrafish. First results show defect in eye development in mutant fish.

Conclusions : These results suggest that CPH1 is a novel gene associated with dominant optic atrophy. Mechanistic study indicated that the mutation in this gene involves severe mitochondrial dysfunction.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.