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Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy

Sorbonne Universités, UPMC University Paris 06, INSERM U968, CNRS UMR 7210, Institut de la Vision, 75012 Paris, France
Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, 115020 Beirut, Lebanon
Magi Euregio, 39100 Bolzano (BZ), Italy
Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC 1423, 75012 Paris, France
Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France
Académie des Sciences-Institut de France, 75006 Paris, France
Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburg, PA 15213, USA
Institute of Ophthalmology, University College of London, London, EC1V 9EL, UK
Authors to whom correspondence should be addressed.
Equal contributions.
Genes 2017, 8(10), 277;
Received: 28 July 2017 / Revised: 4 October 2017 / Accepted: 6 October 2017 / Published: 18 October 2017
We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in KIZ, encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was done by targeted next generation sequencing and subsequent Sanger sequencing validation. KIZ mRNA levels were assessed on blood and serum-deprived human fibroblasts from a control individual and a patient, compound heterozygous for the c.52G>T (p.Glu18*) and c.119_122del (p.Lys40Ilefs*14) mutations in KIZ. KIZ localization, documentation of cilium length and immunoblotting were performed in these two fibroblast cell lines. In addition, PLK1S1 immunolocalization was conducted in mouse retinal cryosections and isolated rod photoreceptors. Analyses of additional RCD patients enabled the identification of two homozygous mutations in KIZ, the known c.226C>T (p.Arg76*) mutation and a novel variant, the c.3G>A (p.Met1?) mutation. Albeit the expression levels of KIZ were three-times lower in the patient than controls in whole blood cells, further analyses in control- and mutant KIZ patient-derived fibroblasts unexpectedly revealed no significant difference between the two genotypes. Furthermore, the averaged monocilia length in the two fibroblast cell lines was similar, consistent with the preserved immunolocalization of KIZ at the basal body of the primary cilia. Analyses in mouse retina and isolated rod photoreceptors showed PLK1S1 localization at the base of the photoreceptor connecting cilium. In conclusion, two additional patients with mutations in KIZ were identified, further supporting that defects in KIZ/PLK1S1, detected at the basal body of the primary cilia in fibroblasts, and the photoreceptor connecting cilium in mouse, respectively, are involved in RCD. However, albeit the mutations were predicted to lead to nonsense mediated mRNA decay, we could not detect changes upon expression levels, protein localization or cilia length in KIZ-mutated fibroblast cells. Together, our findings unveil the limitations of fibroblasts as a cellular model for RCD and call for other models such as induced pluripotent stem cells to shed light on retinal pathogenic mechanisms of KIZ mutations. View Full-Text
Keywords: rod-cone dystrophy; mouse retina; KIZ; PLK1S1; functional characterization rod-cone dystrophy; mouse retina; KIZ; PLK1S1; functional characterization
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MDPI and ACS Style

El Shamieh, S.; Méjécase, C.; Bertelli, M.; Terray, A.; Michiels, C.; Condroyer, C.; Fouquet, S.; Sadoun, M.; Clérin, E.; Liu, B.; Léveillard, T.; Goureau, O.; Sahel, J.-A.; Audo, I.; Zeitz, C. Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy. Genes 2017, 8, 277.

AMA Style

El Shamieh S, Méjécase C, Bertelli M, Terray A, Michiels C, Condroyer C, Fouquet S, Sadoun M, Clérin E, Liu B, Léveillard T, Goureau O, Sahel J-A, Audo I, Zeitz C. Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy. Genes. 2017; 8(10):277.

Chicago/Turabian Style

El Shamieh, Said, Cécile Méjécase, Matteo Bertelli, Angélique Terray, Christelle Michiels, Christel Condroyer, Stéphane Fouquet, Maxime Sadoun, Emmanuelle Clérin, Binqian Liu, Thierry Léveillard, Olivier Goureau, José-Alain Sahel, Isabelle Audo, and Christina Zeitz. 2017. "Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy" Genes 8, no. 10: 277.

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