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

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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.
Keywords
BARDET-BIEDL-SYNDROME, RETINITIS-PIGMENTOSA, LEBER CONGENITAL AMAUROSIS, CONE-ROD DYSTROPHY, GENE, IDENTIFICATION, MODEL, PCR

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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.
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.
Chicago author-date
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.
Chicago author-date (all authors)
Estrada-Cuzcano, Alejandro, Kornelis Neveling, Susanne Kohl, Eyal Banin, Ygal Rotenstreich, Dror Sharon, Tzipora C Falik-Zaccai, Stephanie Hipp, Ronald Roepman, Bernd Wissinger, Stef JF Letteboer, Dorus A Mans, Ellen AW Blokland, Michael P Kwint, Sabine J Gijsen, Ramon AC van Huet, Rob WJ Collin, H Scheffer, Joris A Veltman, Eberhart Zrenner, the European Retinal Disease Consortium, Anneke I den Hollander, B Jeroen Klevering, Frans PM Cremers, Bart Leroy, and Elfride De Baere. 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.
IEEE
[1]
A. Estrada-Cuzcano 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, vol. 90, no. 1, pp. 102–109, 2012.
@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>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.},
  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},
  keywords     = {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},
}

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