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Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects  Konstantinos Nikopoulos, Pietro Farinelli, Basilio.

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Presentation on theme: "Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects  Konstantinos Nikopoulos, Pietro Farinelli, Basilio."— Presentation transcript:

1 Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects 
Konstantinos Nikopoulos, Pietro Farinelli, Basilio Giangreco, Chrysanthi Tsika, Beryl Royer-Bertrand, Martial K. Mbefo, Nicola Bedoni, Ulrika Kjellström, Ikram El Zaoui, Silvio Alessandro Di Gioia, Sara Balzano, Katarina Cisarova, Andrea Messina, Sarah Decembrini, Sotiris Plainis, Styliani V. Blazaki, Muhammad Imran Khan, Shazia Micheal, Karsten Boldt, Marius Ueffing, Alexandre P. Moulin, Frans P.M. Cremers, Ronald Roepman, Yvan Arsenijevic, Miltiadis K. Tsilimbaris, Sten Andréasson, Carlo Rivolta  The American Journal of Human Genetics  Volume 99, Issue 3, Pages (September 2016) DOI: /j.ajhg Copyright © 2016 American Society of Human Genetics Terms and Conditions

2 Figure 1 CEP78 Mutations Pedigrees and electropherograms of the identified DNA changes. Asterisks indicate the site of mutations. Abbreviations are as follows: Mx, mutant alleles; wt, wild-type allele. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2016 American Society of Human Genetics Terms and Conditions

3 Figure 2 Clinical Features of the Analyzed Subjects
(A) Individual KN10. Fundus pictures (at age 53 years) reveal macular coalescent hypochromatic lesions in the right eye and minor macular changes in the left eye. Pure tone audiograms at age 57 years (black lines) and 59 years (red lines) show mild hearing impairment at higher frequencies compared to the normal range for gender and age, indicated by the shaded area.8 (B) Individual 2702r34. Fundus examination at age 65 years highlights attenuated vessels and degenerative changes in the posterior pole. Audiograms at age 66 years (black lines) and 77 years (red lines) show clear hearing loss at most frequencies. Abbreviations are as follows: OD, right eye; OS, left eye; RE, right ear; and LE, left ear. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2016 American Society of Human Genetics Terms and Conditions

4 Figure 3 Immunoblot Analysis of Endogenous CEP78 in Fibroblasts from Affected Individuals Numbers on the left refer to molecular-size markers. Control indicates human fibroblasts from a control individual; HEK293T indicates HEK293 cells containing SV40 large T antigen as a control for specificity of the anti-CEP78 antibody. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2016 American Society of Human Genetics Terms and Conditions

5 Figure 4 CEP78 mRNA Expression in Various Human Tissues and Organs and in the Developing Murine Eye Data are from real-time PCR relative expression analysis, for which GUSB and Hprt1 were used as normalizing genes for (A) and (B), respectively. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2016 American Society of Human Genetics Terms and Conditions

6 Figure 5 CEP78 in Human Cells and Its Interaction with FAM161A
(A) Immunostaining of CEP78 (red dots) and of cone arrestin (green) in a section of human retina. Margins of a cone photoreceptor are highlighted by a dotted line. The scale bar represents 10 μm. (B). Co-immunoprecipitation of endogenous CEP78 and FLAG-tagged FAM161A in HEK293T cells. FLAG-SOX4 is a negative control. Abbreviations are as follows: IP:x, protein targeted by the antibody used in immunoprecipitation; and WB:x, protein or peptide targeted by the antibody used in immunoblots. The single and double asterisks indicate the expected molecular sizes for CEP78 (78 kDa) and the FLAG-FAM161A construct (90 kDa), respectively. (C) Staining of CEP78 (red) and acetylated tubulin (green) in fibroblasts from a control individual, KN10, and 2702r34. CEP78 localizes at the centrioles and at the base of the induced primary cilium. The scale bars represent 5 and 1 μm for regular and magnification panels, respectively. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2016 American Society of Human Genetics Terms and Conditions

7 Figure 6 Analysis of Ciliary Lengths
Fibroblasts from affected subjects display significantly longer primary cilia than those from four unaffected controls, suggesting impaired functionality. The American Journal of Human Genetics  , DOI: ( /j.ajhg ) Copyright © 2016 American Society of Human Genetics Terms and Conditions

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