Mutated CCDC51 Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy.

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4); predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, although usually in association with syndromic disease, unlike our present case. Together, our findings add another ultra-rare mutation implicated in non-syndromic IRD, whose pathogenic mechanism in the retina needs to be further elucidated.

Novel mutation in SLC4A7 gene causing autosomal recessive progressive rod-cone dystrophy.

BACKGROUND: Recent advances in genetic sequencing techniques have improved the overall diagnostic yield for finding genetic causes for inherited retinal dystrophies (IRD). Rod-cone dystrophy is the most common IRD and is characterized by the primary involvement of the rod photoreceptors. Over 80 causal genes have been identified so far giving clinicians insight into the pathogenesis. SLC4A7 encodes a sodium bicarbonate cotransporter responsible acid disposal which, within the retina, is prevalent in the photoreceptor synaptic terminals. Thus far, there have been no published reports of variants in this gene known to cause rod-cone dystrophy. MATERIAL AND METHODS: Case report of a rod-cone dystrophy patient with a novel mutation in SLC4A7, whole exome sequencing with CLIA-certified NGS and Sanger confirmation, and, review of a SLC4A7 knockout mouse model phenotype. RESULTS: A 66-year-old male presented with slowly progressing night blindness, constricted visual field and relatively stable visual acuity. Fundus examination showed diffuse intraretinal pigment in the mid- and peripheral retina, diffuse retinal pigment epithelial atrophy, and intact macula in both eyes. There has been mild macular edema in both eyes which remained stable with the use of topical dorzolamide eyedrops. Whole exome sequencing found, and a subsequent vision panel confirmed, the pathogenic variant to be a homozygous frameshift mutation in SLC4A7 which results in termination of the protein. CONCLUSIONS: We report a case of progressive rod-cone dystrophy caused by a novel mutation in SLC4A7, a gene coding the sodium bicarbonate cotransporter NBC3, underscoring the importance of ion homeostasis for photoreceptor function and maintenance.

[Research progress of treatment strategies for retinitis pigmentosa].

Retinitis pigmentosa (RP) is a genetically heterogeneous group of hereditary retinal disorders characterized by photoreceptor cell death, associated with night blindness, vision loss, progressive peripheral visual field loss and abnormalities in the electroretinogram. A number of gene defects have so far been associated with RP, which cause a progressive loss of rod photoreceptor function, followed by cone photoreceptor dysfunction and eventually complete blindness. The rate of blindness related to RP is high. At present there is no effective therapeutic strategy for RP. In recent years, with the progress of molecular biology technique, many new therapeutic approaches have become promising. This article summarizes the pathogenesis of RP and gives a brief overview of related research progress of RP therapeutic strategies. (Chin J Ophthalmol, 2017, 53: 148-153).