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

Nikopoulos, Konstantinos; Farinelli, Pietro; Giangreco, Basilio; Tsika, Chrysanthi; Royer-Bertrand, Beryl; Mbefo, Martial K; Bedoni, Nicola; Kjellström, Ulrika LU ; El Zaoui, Ikram and Di Gioia, Silvio Alessandro, et al. (2016) In American Journal of Human Genetics 99(3). p.770-776
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... (More)

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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Journal Article
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American Journal of Human Genetics
volume
99
issue
3
pages
7 pages
publisher
Cell Press
external identifiers
  • wos:000383114800023
  • scopus:85008668737
ISSN
0002-9297
DOI
10.1016/j.ajhg.2016.07.009
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English
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yes
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cecbeab6-431c-4ae1-bb0d-ca5b46690998
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2016-11-16 13:38:52
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2017-05-21 04:55:36
@article{cecbeab6-431c-4ae1-bb0d-ca5b46690998,
  abstract     = {<p>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&gt;T (IVS3+1G&gt;T) mutation in intron 3. The Swedish subjects, two siblings, were compound heterozygotes for the nearby mutation c.499+5G&gt;A (IVS3+5G&gt;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.</p>},
  author       = {Nikopoulos, Konstantinos and Farinelli, Pietro and Giangreco, Basilio and Tsika, Chrysanthi and Royer-Bertrand, Beryl and Mbefo, Martial K and Bedoni, Nicola and Kjellström, Ulrika and El Zaoui, Ikram and Di Gioia, Silvio Alessandro and Balzano, Sara and Cisarova, Katarina and Messina, Andrea and Decembrini, Sarah and Plainis, Sotiris and Blazaki, Styliani V and Khan, Muhammad Imran and Micheal, Shazia and Boldt, Karsten and Ueffing, Marius and Moulin, Alexandre P and Cremers, Frans P M and Roepman, Ronald and Arsenijevic, Yvan and Tsilimbaris, Miltiadis K and Andréasson, Sten and Rivolta, Carlo},
  issn         = {0002-9297},
  keyword      = {Journal Article},
  language     = {eng},
  month        = {09},
  number       = {3},
  pages        = {770--776},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2016.07.009},
  volume       = {99},
  year         = {2016},
}