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

Alejandro Estrada-Cuzcano; Kornelia Neveling; Susanne Kohl; Eyal Banin; Ygal Rotenstreich; Dror Sharon; Tzipora C. Falik-Zaccai; Stephanie Hipp; Ronald Roepman; Bernd Wissinger; Stef J.F. Letteboer; Dorus A. Mans; Ellen A.W. Blokland; Michael P. Kwint; Sabine J. Gijsen; Ramon A.C. Van Huet; Rob W.J. Collin; H. Scheffer; Joris A. Veltman; Eberhart Zrenner; Anneke I. Den Hollander; B. Jeroen Klevering; Frans P.M. Cremers

doi:10.1016/j.ajhg.2011.11.015

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

Alejandro Estrada-Cuzcano, Kornelia Neveling, Susanne Kohl, Eyal Banin, Ygal Rotenstreich, Dror Sharon, Tzipora C. Falik-Zaccai, Stephanie Hipp, Ronald Roepman, Bernd Wissinger, Stef J.F. Letteboer, Dorus A. Mans, Ellen A.W. Blokland, Michael P. Kwint, Sabine J. Gijsen, Ramon A.C. Van Huet, Rob W.J. Collin, H. Scheffer, Joris A. Veltman, Eberhart ZrennerAnneke I. Den Hollander, B. Jeroen Klevering, Frans P.M. Cremers

Research output: Contribution to journal › Article › peer-review

75 Scopus citations

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.

Original language	English
Pages (from-to)	102-109
Number of pages	8
Journal	American Journal of Human Genetics
Volume	90
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2011.11.015
State	Published - 13 Jan 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank all participating families, and we thank Emine Bolat, Lisette Hetterschijt, Liliana Mizrahi-Meissonnier, Susanne Roosing, and Theo Peters for their scientific and technical support. We thank Christian Gilissen and Nienke Wieskamp for their excellent bioinformatical analysis and Carsten Janke for antibody GT335. The other members of the European Retinal Disease Consortium are Carmen Ayuso, Sandro Banfi, Tamar Ben-Yosef, Elfride De Baere, Christian Hamel, Chris Inglehearn, Robert K. Koenekoop, Bart P. Leroy, and Carmel Toomes. These studies were supported by the Radboud University Nijmegen Medical Centre (to F.P.M.C. and A.I.d.H.); the European Community's Seventh Framework Programs FP7/2007–2013 under grant agreement number 223143–TECHGENE (to H.S. and J.A.V.) and FP7/2009 under grant agreement number 241955–SYSCILIA (to R.R.); the Netherlands Organization for Health Research and Development ZonMW grants 917-66-363, 911-08-025 (to J.A.V.), and Vidi-917-86-396 (to R.R.); the Foundation Fighting Blindness USA (BR-GE-0510-0489-RAD, to A.I.d.H.; BR-GE-0510-0490-HUJ to D.S.); Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Gelderse Blinden Stichting; Landelijke Stichting voor Blinden en Slechtzienden; Retina Nederland; Stichting Oogfonds Nederland; Stichting Wetenschappelijk Onderzoek het Oogziekenhuis; Rotterdamse Stichting Blindenbelangen; and Stichting AF Deutman Researchfonds Oogheelkunde (to F.P.M.C. and A.I.d.H.).

Funding

We thank all participating families, and we thank Emine Bolat, Lisette Hetterschijt, Liliana Mizrahi-Meissonnier, Susanne Roosing, and Theo Peters for their scientific and technical support. We thank Christian Gilissen and Nienke Wieskamp for their excellent bioinformatical analysis and Carsten Janke for antibody GT335. The other members of the European Retinal Disease Consortium are Carmen Ayuso, Sandro Banfi, Tamar Ben-Yosef, Elfride De Baere, Christian Hamel, Chris Inglehearn, Robert K. Koenekoop, Bart P. Leroy, and Carmel Toomes. These studies were supported by the Radboud University Nijmegen Medical Centre (to F.P.M.C. and A.I.d.H.); the European Community's Seventh Framework Programs FP7/2007–2013 under grant agreement number 223143–TECHGENE (to H.S. and J.A.V.) and FP7/2009 under grant agreement number 241955–SYSCILIA (to R.R.); the Netherlands Organization for Health Research and Development ZonMW grants 917-66-363, 911-08-025 (to J.A.V.), and Vidi-917-86-396 (to R.R.); the Foundation Fighting Blindness USA (BR-GE-0510-0489-RAD, to A.I.d.H.; BR-GE-0510-0490-HUJ to D.S.); Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Gelderse Blinden Stichting; Landelijke Stichting voor Blinden en Slechtzienden; Retina Nederland; Stichting Oogfonds Nederland; Stichting Wetenschappelijk Onderzoek het Oogziekenhuis; Rotterdamse Stichting Blindenbelangen; and Stichting AF Deutman Researchfonds Oogheelkunde (to F.P.M.C. and A.I.d.H.).

Funders	Funder number
European Community's Seventh Framework Programs FP7/2007
FP7/2009
Netherlands Organization for Health Research and Development ZonMW	917-66-363, 911-08-025
Radboud University Nijmegen Medical Centre
Seventh Framework Programme	223143, 241955
Foundation Fighting Blindness	BR-GE-0510-0489-RAD, BR-GE-0510-0490-HUJ
Algemene Nederlandse Vereniging ter voorkoming van Blindheid
Gelderse Blinden Stichting
Landelijke Stichting voor Blinden en Slechtzienden
Stichting A.F. Deutman Oogheelkunde Researchfonds
Rotterdamse Stichting Blindenbelangen
Stichting Wetenschappelijk Onderzoek Oogziekenhuis

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10.1016/j.ajhg.2011.11.015

Cite this

Estrada-Cuzcano, A., Neveling, K., Kohl, S., Banin, E., Rotenstreich, Y., Sharon, D., Falik-Zaccai, T. C., Hipp, S., Roepman, R., Wissinger, B., Letteboer, S. J. F., Mans, D. A., Blokland, E. A. W., Kwint, M. P., Gijsen, S. J., Van Huet, R. A. C., Collin, R. W. J., Scheffer, H., Veltman, J. A., ... Cremers, F. P. M. (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. https://doi.org/10.1016/j.ajhg.2011.11.015

@article{7096f1e86dbf497eb32055ad814a380e,

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

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 = "Alejandro Estrada-Cuzcano and Kornelia Neveling and Susanne Kohl and Eyal Banin and Ygal Rotenstreich and Dror Sharon and Falik-Zaccai, {Tzipora C.} and Stephanie Hipp and Ronald Roepman and Bernd Wissinger and Letteboer, {Stef J.F.} and Mans, {Dorus A.} and Blokland, {Ellen A.W.} and Kwint, {Michael P.} and Gijsen, {Sabine J.} and {Van Huet}, {Ramon A.C.} and Collin, {Rob W.J.} and H. Scheffer and Veltman, {Joris A.} and Eberhart Zrenner and {Den Hollander}, {Anneke I.} and Klevering, {B. Jeroen} and Cremers, {Frans P.M.}",

note = "Funding Information: We thank all participating families, and we thank Emine Bolat, Lisette Hetterschijt, Liliana Mizrahi-Meissonnier, Susanne Roosing, and Theo Peters for their scientific and technical support. We thank Christian Gilissen and Nienke Wieskamp for their excellent bioinformatical analysis and Carsten Janke for antibody GT335. The other members of the European Retinal Disease Consortium are Carmen Ayuso, Sandro Banfi, Tamar Ben-Yosef, Elfride De Baere, Christian Hamel, Chris Inglehearn, Robert K. Koenekoop, Bart P. Leroy, and Carmel Toomes. These studies were supported by the Radboud University Nijmegen Medical Centre (to F.P.M.C. and A.I.d.H.); the European Community's Seventh Framework Programs FP7/2007–2013 under grant agreement number 223143–TECHGENE (to H.S. and J.A.V.) and FP7/2009 under grant agreement number 241955–SYSCILIA (to R.R.); the Netherlands Organization for Health Research and Development ZonMW grants 917-66-363, 911-08-025 (to J.A.V.), and Vidi-917-86-396 (to R.R.); the Foundation Fighting Blindness USA (BR-GE-0510-0489-RAD, to A.I.d.H.; BR-GE-0510-0490-HUJ to D.S.); Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Gelderse Blinden Stichting; Landelijke Stichting voor Blinden en Slechtzienden; Retina Nederland; Stichting Oogfonds Nederland; Stichting Wetenschappelijk Onderzoek het Oogziekenhuis; Rotterdamse Stichting Blindenbelangen; and Stichting AF Deutman Researchfonds Oogheelkunde (to F.P.M.C. and A.I.d.H.). ",

year = "2012",

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doi = "10.1016/j.ajhg.2011.11.015",

language = "אנגלית",

volume = "90",

pages = "102--109",

journal = "American Journal of Human Genetics",

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Estrada-Cuzcano, A, Neveling, K, Kohl, S, Banin, E, Rotenstreich, Y, Sharon, D, Falik-Zaccai, TC, Hipp, S, Roepman, R, Wissinger, B, Letteboer, SJF, Mans, DA, Blokland, EAW, Kwint, MP, Gijsen, SJ, Van Huet, RAC, Collin, RWJ, Scheffer, H, Veltman, JA, Zrenner, E, Den Hollander, AI, Klevering, BJ & Cremers, FPM 2012, '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. https://doi.org/10.1016/j.ajhg.2011.11.015

TY - JOUR

T1 - Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement

AU - Estrada-Cuzcano, Alejandro

AU - Neveling, Kornelia

AU - Kohl, Susanne

AU - Banin, Eyal

AU - Rotenstreich, Ygal

AU - Sharon, Dror

AU - Falik-Zaccai, Tzipora C.

AU - Hipp, Stephanie

AU - Roepman, Ronald

AU - Wissinger, Bernd

AU - Letteboer, Stef J.F.

AU - Mans, Dorus A.

AU - Blokland, Ellen A.W.

AU - Kwint, Michael P.

AU - Gijsen, Sabine J.

AU - Van Huet, Ramon A.C.

AU - Collin, Rob W.J.

AU - Scheffer, H.

AU - Veltman, Joris A.

AU - Zrenner, Eberhart

AU - Den Hollander, Anneke I.

AU - Klevering, B. Jeroen

AU - Cremers, Frans P.M.

N1 - Funding Information: We thank all participating families, and we thank Emine Bolat, Lisette Hetterschijt, Liliana Mizrahi-Meissonnier, Susanne Roosing, and Theo Peters for their scientific and technical support. We thank Christian Gilissen and Nienke Wieskamp for their excellent bioinformatical analysis and Carsten Janke for antibody GT335. The other members of the European Retinal Disease Consortium are Carmen Ayuso, Sandro Banfi, Tamar Ben-Yosef, Elfride De Baere, Christian Hamel, Chris Inglehearn, Robert K. Koenekoop, Bart P. Leroy, and Carmel Toomes. These studies were supported by the Radboud University Nijmegen Medical Centre (to F.P.M.C. and A.I.d.H.); the European Community's Seventh Framework Programs FP7/2007–2013 under grant agreement number 223143–TECHGENE (to H.S. and J.A.V.) and FP7/2009 under grant agreement number 241955–SYSCILIA (to R.R.); the Netherlands Organization for Health Research and Development ZonMW grants 917-66-363, 911-08-025 (to J.A.V.), and Vidi-917-86-396 (to R.R.); the Foundation Fighting Blindness USA (BR-GE-0510-0489-RAD, to A.I.d.H.; BR-GE-0510-0490-HUJ to D.S.); Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Gelderse Blinden Stichting; Landelijke Stichting voor Blinden en Slechtzienden; Retina Nederland; Stichting Oogfonds Nederland; Stichting Wetenschappelijk Onderzoek het Oogziekenhuis; Rotterdamse Stichting Blindenbelangen; and Stichting AF Deutman Researchfonds Oogheelkunde (to F.P.M.C. and A.I.d.H.).

PY - 2012/1/13

Y1 - 2012/1/13

N2 - 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.

AB - 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.

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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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Bibliographical note

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