title: Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy.
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.
authors.affiliation: 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.
authors.forename: Said
authors.initials: S
authors.lastname: El Shamieh
authors.affiliation: 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.
authors.forename: Marion
authors.initials: M
authors.lastname: Neuillé
authors.affiliation: 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.
authors.forename: Angélique
authors.initials: A
authors.lastname: Terray
authors.affiliation: 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.
authors.forename: Elise
authors.initials: E
authors.lastname: Orhan
authors.affiliation: 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.
authors.forename: Christel
authors.initials: C
authors.lastname: Condroyer
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Démontant
authors.affiliation: 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.
authors.forename: Christelle
authors.initials: C
authors.lastname: Michiels
authors.affiliation: 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.
authors.forename: Aline
authors.initials: A
authors.lastname: Antonio
authors.affiliation: 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.
authors.forename: Fiona
authors.initials: F
authors.lastname: Boyard
authors.affiliation: 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.
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Lancelot
authors.affiliation: IntegraGen SA, Genopole Campus 1, Building G8, Evry 91030, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Letexier
authors.affiliation: IntegraGen SA, Genopole Campus 1, Building G8, Evry 91030, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Saraiva
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Léveillard
authors.affiliation: 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.
authors.forename: Saddek
authors.initials: S
authors.lastname: Mohand-Saïd
authors.affiliation: 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.
authors.forename: Olivier
authors.initials: O
authors.lastname: Goureau
authors.affiliation: 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.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: 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.
authors.forename: Christina
authors.initials: C
authors.lastname: Zeitz
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Audo
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D018389:Codon, Nonsense; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D051379:Mice; D010375:Pedigree; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics*; D059467:Transcriptome
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; C000588439:KIZ protein, human