Next Article in Journal
A DNA Structural Alphabet Distinguishes Structural Features of DNA Bound to Regulatory Proteins and in the Nucleosome Core Particle
Next Article in Special Issue
Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies
Previous Article in Journal
Transcriptomic Analysis of Long Non-Coding RNAs and Coding Genes Uncovers a Complex Regulatory Network That Is Involved in Maize Seed Development
Previous Article in Special Issue
The Genetic Basis of Pericentral Retinitis Pigmentosa—A Form of Mild Retinitis Pigmentosa
Article Menu
Issue 10 (October) cover image

Export Article

Open AccessArticle
Genes 2017, 8(10), 277; doi:10.3390/genes8100277

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

1
Sorbonne Universités, UPMC University Paris 06, INSERM U968, CNRS UMR 7210, Institut de la Vision, 75012 Paris, France
2
Department of Medical Laboratory Technology, Faculty of Health Sciences, Beirut Arab University, 115020 Beirut, Lebanon
3
Magi Euregio, 39100 Bolzano (BZ), Italy
4
Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, DHU Sight Restore, INSERM-DHOS CIC 1423, 75012 Paris, France
5
Fondation Ophtalmologique Adolphe de Rothschild, 75019 Paris, France
6
Académie des Sciences-Institut de France, 75006 Paris, France
7
Department of Ophthalmology, The University of Pittsburgh School of Medicine, Pittsburg, PA 15213, USA
8
Institute of Ophthalmology, University College of London, London, EC1V 9EL, UK
Equal contributions.
*
Authors to whom correspondence should be addressed.
Received: 28 July 2017 / Revised: 4 October 2017 / Accepted: 6 October 2017 / Published: 18 October 2017
View Full-Text   |   Download PDF [7677 KB, uploaded 18 October 2017]   |  

Abstract

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
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Genes EISSN 2073-4425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top