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

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Title:	Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement.
Author(s):	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.; Huet, R.A.C. van; Collin, R.W.J. ; Scheffer, H. ; Veltman, J.A. ; Zrenner, E.; Hollander, A.I. den ; Klevering, B.J. ; Cremers, F.P.M.
Publication year:	2012
Source:	American Journal of Human Genetics, vol. 90, iss. 1, (2012), pp. 102-109
ISSN:	0002-9297
DOI:	https://doi.org/10.1016/j.ajhg.2011.11.015
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/108768
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Subject:	IGMD 3: Genomic disorders and inherited multi-system disorders IGMD 3: Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory NCEBP 2: Evaluation of complex medical interventions NCMLS 6: Genetics and epigenetic pathways of disease NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders NCEBP 2: Evaluation of complex medical interventions IGMD 3: Genomic disorders and inherited multi-system disorders
Organization:	Human Genetics Ophthalmology
Journal title:	American Journal of Human Genetics
Volume:	vol. 90
Issue:	iss. 1
Page start:	p. 102
Page end:	p. 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.