2. Academic Validation
  3. Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects

Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects

  • Am J Hum Genet. 2016 Sep 1;99(3):770-776. doi: 10.1016/j.ajhg.2016.07.009.
Konstantinos Nikopoulos 1,  Pietro Farinelli 1,  Basilio Giangreco 2,  Chrysanthi Tsika 3,  Beryl Royer-Bertrand 4,  Martial K Mbefo 5,  Nicola Bedoni 1,  Ulrika Kjellström 6,  Ikram El Zaoui 1,  Silvio Alessandro Di Gioia 1,  Sara Balzano 1,  Katarina Cisarova 1,  Andrea Messina 7,  Sarah Decembrini 5,  Sotiris Plainis 3,  Styliani V Blazaki 3,  Muhammad Imran Khan 8,  Shazia Micheal 8,  Karsten Boldt 9,  Marius Ueffing 9,  Alexandre P Moulin 10,  Frans P M Cremers 11,  Ronald Roepman 8,  Yvan Arsenijevic 5,  Miltiadis K Tsilimbaris 3,  Sten Andréasson 6,  Carlo Rivolta 12
Affiliations

Affiliations

  • 1 Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne, Switzerland.
  • 2 Center for Psychiatric Neuroscience, Department of Psychiatry, Lausanne University Hospital, 1008 Lausanne, Switzerland.
  • 3 Department of Ophthalmology, Medical School, University of Crete, 71003 Heraklion, Greece.
  • 4 Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne, Switzerland; Center for Molecular Diseases, Lausanne University Hospital, 1011 Lausanne, Switzerland.
  • 5 Unit of Gene Therapy and Stem Cell Biology, Jules Gonin Ophthalmic Hospital, 1004 Lausanne, Switzerland.
  • 6 Lund University, Skane University Hospital, Department of Ophthalmology, 20502 Lund, Sweden.
  • 7 Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland.
  • 8 Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands.
  • 9 Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen, 72074 Tuebingen, Germany.
  • 10 Department of Ophthalmology, Jules Gonin Ophthalmic Hospital, 1004 Lausanne, Switzerland.
  • 11 Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands; Donders Center for Neuroscience, Radboud University, 6525EN Nijmegen, The Netherlands.
  • 12 Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne, Switzerland. Electronic address: [email protected].
PMID: 27588451 DOI: 10.1016/j.ajhg.2016.07.009
Abstract

Cone-rod degeneration (CRD) belongs to the disease spectrum of retinal degenerations, a group of hereditary disorders characterized by an extreme clinical and genetic heterogeneity. It mainly differentiates from other retinal dystrophies, and in particular from the more frequent disease retinitis pigmentosa, because cone photoreceptors degenerate at a higher rate than rod photoreceptors, causing severe deficiency of central vision. After exome analysis of a cohort of individuals with CRD, we identified biallelic mutations in the orphan gene CEP78 in three subjects from two families: one from Greece and another from Sweden. The Greek subject, from the island of Crete, was homozygous for the c.499+1G>T (IVS3+1G>T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G>A (IVS3+5G>A) and for the frameshift-causing variant c.633delC (p.Trp212Glyfs(∗)18). In addition to CRD, these three individuals had hearing loss or hearing deficit. Immunostaining highlighted the presence of CEP78 in the inner segments of retinal photoreceptors, predominantly of cones, and at the base of the primary cilium of fibroblasts. Interaction studies also showed that CEP78 binds to FAM161A, another ciliary protein associated with retinal degeneration. Finally, analysis of skin fibroblasts derived from affected individuals revealed abnormal ciliary morphology, as compared to that of control cells. Altogether, our data strongly suggest that mutations in CEP78 cause a previously undescribed clinical entity of a ciliary nature characterized by blindness and deafness but clearly distinct from Usher syndrome, a condition for which visual impairment is due to retinitis pigmentosa.

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