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Am J Hum Genet. 2014 Apr 3;94(4):625-33. doi: 10.1016/j.ajhg.2014.03.005. Epub 2014 Mar 27.

Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy.

Author information

1
Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France; Centre National de la Recherche Scientifique UMR_7210, Paris 75012, France; Institut de la Vision UMR_S 968, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France.
2
IntegraGen SA, Genopole Campus 1, Building G8, Evry 91030, France.
3
Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France; Centre National de la Recherche Scientifique UMR_7210, Paris 75012, France; Institut de la Vision UMR_S 968, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Institut National de la Santé et de la Recherche Médicale and Direction de l'Hospitalisation et de l'Organisation des Soins Centre d'Investigation Clinique 1423, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris 75012, France.
4
Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France; Centre National de la Recherche Scientifique UMR_7210, Paris 75012, France; Institut de la Vision UMR_S 968, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Institut National de la Santé et de la Recherche Médicale and Direction de l'Hospitalisation et de l'Organisation des Soins Centre d'Investigation Clinique 1423, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris 75012, France; Fondation Ophtalmologique Adolphe de Rothschild, Paris 75019, France; Académie des Sciences, Institut de France, Paris 75006, France; University College London Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK.
5
Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France; Centre National de la Recherche Scientifique UMR_7210, Paris 75012, France; Institut de la Vision UMR_S 968, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France. Electronic address: christina.zeitz@inserm.fr.
6
Institut National de la Santé et de la Recherche Médicale U968, Paris 75012, France; Centre National de la Recherche Scientifique UMR_7210, Paris 75012, France; Institut de la Vision UMR_S 968, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, Paris 75012, France; Institut National de la Santé et de la Recherche Médicale and Direction de l'Hospitalisation et de l'Organisation des Soins Centre d'Investigation Clinique 1423, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Paris 75012, France; University College London Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK. Electronic address: isabelle.audo@inserm.fr.

Abstract

Rod-cone dystrophy (RCD), also known as retinitis pigmentosa, is a progressive inherited retinal disorder characterized by photoreceptor cell death and genetic heterogeneity. Mutations in many genes have been implicated in the pathophysiology of RCD, but several others remain to be identified. Herein, we applied whole-exome sequencing to a consanguineous family with one subject affected with RCD and identified a homozygous nonsense mutation, c.226C>T (p.Arg76(∗)), in KIZ, which encodes centrosomal protein kizuna. Subsequent Sanger sequencing of 340 unrelated individuals with sporadic and autosomal-recessive RCD identified two other subjects carrying pathogenic variants in KIZ: one with the same homozygous nonsense mutation (c.226C>T [p.Arg76(∗)]) and another with compound-heterozygous mutations c.119_122delAACT (p.Lys40Ilefs(∗)14) and c.52G>T (p.Glu18(∗)). Transcriptomic analysis in mice detected mRNA levels of the mouse ortholog (Plk1s1) in rod photoreceptors, as well as its decreased expression when photoreceptors degenerated in rd1 mice. The presence of the human KIZ transcript was confirmed by quantitative RT-PCR in the retina, the retinal pigment epithelium, fibroblasts, and whole-blood cells (highest expression was in the retina). RNA in situ hybridization demonstrated the presence of Plk1s1 mRNA in the outer nuclear layer of the mouse retina. Immunohistology revealed KIZ localization at the basal body of the cilia in human fibroblasts, thus shedding light on another ciliary protein implicated in autosomal-recessive RCD.

PMID:
24680887
PMCID:
PMC3980423
DOI:
10.1016/j.ajhg.2014.03.005
[Indexed for MEDLINE]
Free PMC Article

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