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

El Shamieh, Said and Méjécase, Cécile and Bertelli, Matteo and Terray, Angélique and Michiels, Christelle and Condroyer, Christel and Fouquet, Stéphane and Sadoun, Maxime and Clérin, Emmanuelle and Liu, Binqian and Léveillard, Thierry and Goureau, Olivier and Sahel, José-Alain and Audo, Isabelle and Zeitz, Christina (2017) Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy. Genes, 8 (10). p. 277. ISSN 2073-4425

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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.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
El Shamieh, Said
Méjécase, Cécile
Bertelli, Matteo
Terray, Angélique
Michiels, Christelle
Condroyer, Christel
Fouquet, Stéphane
Sadoun, Maxime
Clérin, Emmanuelle
Liu, Binqian
Léveillard, Thierry
Goureau, Olivier
Sahel, José
Audo, Isabelle
Zeitz, Christina
Date: 18 October 2017
Date Type: Publication
Journal or Publication Title: Genes
Volume: 8
Number: 10
Publisher: MDPI AG
Page Range: p. 277
DOI or Unique Handle: 10.3390/genes8100277
Schools and Programs: School of Medicine > Ophthalmology
Refereed: Yes
Uncontrolled Keywords: rod-cone dystrophy, mouse retina, KIZ, PLK1S1, functional characterization
ISSN: 2073-4425
Official URL:
Article Type: Research Article
Date Deposited: 14 Dec 2021 19:44
Last Modified: 14 Dec 2021 19:44


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