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

Prasanthi Namburi, Rinki Ratnapriya, Samer Khateb, Csilla H. Lazar, Yael Kinarty, Alexey Obolensky, Inbar Erdinest, Devorah Marks-Ohana, Eran Pras, Tamar Ben-Yosef, Hadas Newman, Menachem Gross, Anand Swaroop, Eyal Banin*, Dror Sharon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.Asp298Valfs17). 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.

Original languageEnglish
Pages (from-to)777-784
Number of pages8
JournalAmerican Journal of Human Genetics
Volume99
Issue number3
DOIs
StatePublished - 2016

Funding

FundersFunder number
Israeli Ministry of Health and the Lirot association300009177
National Institutes of Health
National Eye InstituteZIAEY000546
Foundation Fighting BlindnessBR-GE-0214-0639
United States - Israel Binational Science Foundation2011202
Israel Science Foundation2154/15

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