A CCDC51 frameshift variant as a candidate gene defect for autosomal recessive rod-cone dystrophy

Abstract

Purpose : The purpose of this work was to identify the gene defect underlying rod-cone dystrophy (RCD) in a female patient with no disease causing variants in 123 genes implicated in inherited retinal disorders and to provide transcriptomic and immunolocalization data to underpin the best candidate.

Methods : The patient originating from a consanguineous family underwent full ophthalmic examination. Informed consents were obtained from the patient and available family members. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethic committee. The DNA of the index patient was investigated for large duplications, deletions and homozygous regions by array comparative genomic hybridization (CGH). Subsequently, whole exome sequencing (WES) was performed on the DNA of the index patient, the unaffected brother and father. Co-segregation analyses in all available family members were performed by Sanger sequencing. The expression of CCDC51 was investigated in transcriptomic databases and by RT-PCR experiments. Immunolocalization studies were performed using a commercially available antibody and mitochondrial markers on fibroblasts and retinal sections.

Results : The patient represented a relative mild RCD. Array CGH revealed no large duplications or deletions, but several large homozygous regions. WES identified a frameshift variant, c.244_246delins17 p.W82Vfs*4 in CCDC51, coding for a coiled-coil domain containing 51 protein located in an 18 Mb large homozygous region on chromosome 3. The gene is expressed in different tissues, including retina. It codes for a mitochondrial protein as shown in fibroblasts and retinal sections, where it is located in the inner segments (IS) of the photoreceptors.

Conclusions : Mitochondria are important intracellular organelles and the major source for cellular energy production through oxidative phosphorylation. In the eye, mitochondria are located in the retinal pigment epithelium and the IS of photoreceptors. Mitochondrial proteins have been implicated in retinal disorders, most of them however leading to syndromic forms. General detailed clinical examination of the patient with RCD and CCDC51 mutations will be performed to exclude a syndromic disease. Functional studies on control and patient fibroblasts and/or animal models are needed to characterize the novel mitochondrial protein and the pathogenic mechanism underlying RCD.

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