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

Autor: Alexandre Moulin, Styliani V. Blazaki, Ikram El Zaoui, Yvan Arsenijevic, Basilio Giangreco, Konstantinos Nikopoulos, Sotiris Plainis, Katarina Cisarova, Ulrika Kjellström, Pietro Farinelli, Shazia Micheal, Frans P.M. Cremers, Silvio Alessandro Di Gioia, Sara Balzano, Andrea Messina, Martial Mbefo, Marius Ueffing, Sarah Decembrini, Muhammad Imran Khan, Sten Andréasson, Carlo Rivolta, Chrysanthi Tsika, Beryl Royer-Bertrand, Nicola Bedoni, Miltiadis K. Tsilimbaris, Karsten Boldt, Ronald Roepman
Rok vydání: 2016
Předmět:
0301 basic medicine
Retinal degeneration
Male
Pathology
genetic structures
Usher syndrome
Cell Cycle Proteins
030105 genetics & heredity
Compound heterozygosity
Eye
Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12]
Cohort Studies
chemistry.chemical_compound
Mice
Exome
Genetics(clinical)
Genetics (clinical)
Genetics
Greece
Cilium
Homozygote
Middle Aged
Pedigree
Female
Usher Syndromes
Retinal Dystrophies
Protein Binding
medicine.medical_specialty
Heterozygote
Hearing Loss
Sensorineural
Biology
03 medical and health sciences
Report
Retinitis pigmentosa
medicine
Cadaver
Animals
Humans
Cilia
RNA
Messenger
Sensory disorders Radboud Institute for Molecular Life Sciences [Radboudumc 12]
Aged
Alleles
Cell Cycle Proteins/genetics
Cell Cycle Proteins/metabolism
Cilia/pathology
Cone-Rod Dystrophies/complications
Cone-Rod Dystrophies/genetics
Cone-Rod Dystrophies/pathology
Cone-Rod Dystrophies/physiopathology
Exome/genetics
Eye/embryology
Eye/metabolism
Eye Proteins/metabolism
Fibroblasts/pathology
Hearing Loss
Sensorineural/complications
Hearing Loss
Sensorineural/genetics
Hearing Loss
Sensorineural/pathology
Hearing Loss
Sensorineural/physiopathology
Introns/genetics
Mutation/genetics
RNA
Messenger/analysis
Sweden
Transcriptome
Usher Syndromes/pathology
Eye Proteins
Genetic heterogeneity
Retinal
Fibroblasts
medicine.disease
eye diseases
Introns
030104 developmental biology
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]
chemistry
Mutation
sense organs
Cone-Rod Dystrophies
Zdroj: American Journal of Human Genetics, 99, 770-6
American journal of human genetics, vol. 99, no. 3, pp. 770-776
American Journal of Human Genetics, 99, 3, pp. 770-6
ISSN: 0002-9297
DOI: 10.1016/j.ajhg.2016.07.009
Popis: Item does not contain fulltext 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.
Databáze: OpenAIRE
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