Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss

Am J Hum Genet. 2016 Sep 1;99(3):777-784. doi: 10.1016/j.ajhg.2016.07.010.

Prasanthi Namburi ¹, Rinki Ratnapriya ², Samer Khateb ¹, Csilla H Lazar ³, Yael Kinarty ⁴, Alexey Obolensky ¹, Inbar Erdinest ¹, Devorah Marks-Ohana ¹, Eran Pras ⁵, Tamar Ben-Yosef ⁶, Hadas Newman ⁷, Menachem Gross ⁸, Anand Swaroop ², Eyal Banin ⁹, Dror Sharon ¹⁰

Affiliations

1 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
2 Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892-0610, USA.
3 Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892-0610, USA; Molecular Biology Center, Interdisciplinary Research Institute on Bio-Nano Sciences, Babes-Bolyai-University, 400271, Cluj-Napoca, Romania.
4 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel; Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
5 Department of Ophthalmology, Assaf Harofeh Medical Center, Zerifin, 70300, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel.
6 The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525433, Israel.
7 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel; Department of Ophthalmology, Tel-Aviv Medical Center, Tel-Aviv, 64239, Israel.
8 Department of Otolaryngology-Head and Neck Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
9 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel. Electronic address: [email protected].
10 Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel. Electronic address: [email protected].

PMID: 27588452 DOI: 10.1016/j.ajhg.2016.07.010

Abstract

Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL. RT-PCR analysis of CEP78 in blood leukocytes of affected individuals revealed that the c.893-1G>A mutation causes exon 7 skipping leading to deletion of 65bp, predicted to result in a frameshift and therefore a truncated protein (p.Asp298Valfs(∗)17). RT-PCR analysis of 17 human tissues demonstrated ubiquitous expression of different CEP78 transcripts. RNA-seq analysis revealed three transcripts in the human retina and relatively higher expression in S-cone-like photoreceptors of Nrl-knockout retina compared to rods. Immunohistochemistry studies in the human retina showed intense labeling of cone inner segments compared to rods. CEP78 was reported previously to interact with c-nap1, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome. We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome.

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