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Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement

Alejandro Estrada-Cuzcano, Kornelis Neveling, Susanne Kohl, Eyal Banin, Ygal Rotenstreich, Dror Sharon, Tzipora C Falik-Zaccai, Stephanie Hipp, Ronald Roepman and Bernd Wissinger, et al. (2012) AMERICAN JOURNAL OF HUMAN GENETICS. 90(1). p.102-109
abstract
Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166*]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
BARDET-BIEDL-SYNDROME, RETINITIS-PIGMENTOSA, LEBER CONGENITAL AMAUROSIS, CONE-ROD DYSTROPHY, GENE, IDENTIFICATION, MODEL, PCR
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
90
issue
1
pages
102 - 109
Web of Science type
Article
Web of Science id
000299409100010
JCR category
GENETICS & HEREDITY
JCR impact factor
11.202 (2012)
JCR rank
7/161 (2012)
JCR quartile
1 (2012)
ISSN
0002-9297
DOI
10.1016/j.ajhg.2011.11.015
language
English
UGent publication?
no
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
2086266
handle
http://hdl.handle.net/1854/LU-2086266
date created
2012-04-13 13:58:13
date last changed
2012-04-17 14:28:45
@article{2086266,
  abstract     = {Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T{\textrangle}A [p.Leu166*]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A{\textrangle}G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C{\textrangle}T [p.Arg177Trp]; c.545A{\textrangle}G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A{\textrangle}G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.},
  author       = {Estrada-Cuzcano, Alejandro and Neveling, Kornelis and Kohl, Susanne and Banin, Eyal and Rotenstreich, Ygal and Sharon, Dror and Falik-Zaccai, Tzipora C and Hipp, Stephanie and Roepman, Ronald and Wissinger, Bernd and Letteboer, Stef JF and Mans, Dorus A and Blokland, Ellen AW and Kwint, Michael P and Gijsen, Sabine J and van Huet, Ramon AC and Collin, Rob WJ and Scheffer, H and Veltman, Joris A and Zrenner, Eberhart and European Retinal Disease Consortium, the and den Hollander, Anneke I and Klevering, B Jeroen and Cremers, Frans PM and Leroy, Bart and De Baere, Elfride},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {BARDET-BIEDL-SYNDROME,RETINITIS-PIGMENTOSA,LEBER CONGENITAL AMAUROSIS,CONE-ROD DYSTROPHY,GENE,IDENTIFICATION,MODEL,PCR},
  language     = {eng},
  number       = {1},
  pages        = {102--109},
  title        = {Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2011.11.015},
  volume       = {90},
  year         = {2012},
}

Chicago
Estrada-Cuzcano, Alejandro, Kornelis Neveling, Susanne Kohl, Eyal Banin, Ygal Rotenstreich, Dror Sharon, Tzipora C Falik-Zaccai, et al. 2012. “Mutations in C8orf37, Encoding a Ciliary Protein, Are Associated with Autosomal-recessive Retinal Dystrophies with Early Macular Involvement.” American Journal of Human Genetics 90 (1): 102–109.
APA
Estrada-Cuzcano, A., Neveling, K., Kohl, S., Banin, E., Rotenstreich, Y., Sharon, D., Falik-Zaccai, T. C., et al. (2012). Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement. AMERICAN JOURNAL OF HUMAN GENETICS, 90(1), 102–109.
Vancouver
1.
Estrada-Cuzcano A, Neveling K, Kohl S, Banin E, Rotenstreich Y, Sharon D, et al. Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement. AMERICAN JOURNAL OF HUMAN GENETICS. 2012;90(1):102–9.
MLA
Estrada-Cuzcano, Alejandro, Kornelis Neveling, Susanne Kohl, et al. “Mutations in C8orf37, Encoding a Ciliary Protein, Are Associated with Autosomal-recessive Retinal Dystrophies with Early Macular Involvement.” AMERICAN JOURNAL OF HUMAN GENETICS 90.1 (2012): 102–109. Print.