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.