title: Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss.
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.
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Prasanthi
authors: P
authors: Namburi
authors: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892-0610, USA.
authors: Rinki
authors: R
authors: Ratnapriya
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Samer
authors: S
authors: Khateb
authors: 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.
authors: Csilla H
authors: CH
authors: Lazar
authors: 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.
authors: Yael
authors: Y
authors: Kinarty
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Alexey
authors: A
authors: Obolensky
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Inbar
authors: I
authors: Erdinest
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Devorah
authors: D
authors: Marks-Ohana
authors: Department of Ophthalmology, Assaf Harofeh Medical Center, Zerifin, 70300, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel.
authors: Eran
authors: E
authors: Pras
authors: The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525433, Israel.
authors: Tamar
authors: T
authors: Ben-Yosef
authors: Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, 6997801, Israel; Department of Ophthalmology, Tel-Aviv Medical Center, Tel-Aviv, 64239, Israel.
authors: Hadas
authors: H
authors: Newman
authors: Department of Otolaryngology-Head and Neck Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel.
authors: Menachem
authors: M
authors: Gross
authors: Neurobiology-Neurodegeneration & Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892-0610, USA.
authors: Anand
authors: A
authors: Swaroop
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel. Electronic address: banine@cc.huji.ac.il.
authors: Eyal
authors: E
authors: Banin
authors: Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, 91120, Israel. Electronic address: dror.sharon1@gmail.com.
authors: Dror
authors: D
authors: Sharon
mesh_terms: D000328:Adult; D000483:Alleles; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D000071700:Cone-Rod Dystrophies / Q000235:genetics* / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology; D006720:Homozygote; D006801:Humans; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D017384:Sequence Deletion / Q000235:genetics*; D052245:Usher Syndromes / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D001324:Autoantigens; C000618001:CEP78 protein, human; D018797:Cell Cycle Proteins; C111329:CEP250 protein, human; D012333:RNA, Messenger