Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations

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Mainzer-Saldino Syndrome Is a Ciliopathy Caused by IFT140 Mutations Isabelle Perrault, Sophie Saunier, Sylvain Hanein, Emilie Filhol, Albane A. Bizet, Felicity Collins, Mustafa A.M. Salih, Sylvie Gerber, Nathalie Delphin, Karine Bigot, Christophe Orssaud, Eduardo Silva, Véronique Baudouin, Machteld M. Oud, Nora Shannon, Martine Le Merrer, Olivier Roche, Christine Pietrement, Jamal Goumid, Clarisse Baumann, Christine Bole-Feysot, Patrick Nitschke, Mohammed Zahrate, Philip Beales, Heleen H. Arts, Arnold Munnich, Josseline Kaplan, Corinne Antignac, Valérie Cormier-Daire, Jean-Michel Rozet The American Journal of Human Genetics Volume 90, Issue 5, Pages 864-870 (May 2012) DOI: 10.1016/j.ajhg.2012.03.006 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical and Radiological Manifestations of MSS-Affected Individuals (A and B) Photograph and thorax X-rays of affected individual FI1 at 17 years of age showing narrow chest. (C–E) Hip X-rays of affected individuals FI1 (17 years), FIII1 (9 years), and FIII2 (5 years) showing flattened femoral epiphyses (C–D) and wide femoral neck with areas of sclerosis in the metaphyseal region (arrows). (F–J) Hand X-ray of affected individuals FI1, FIII1, FIII2, FII1, and FV1 showing PCSE (arrows). (K–N) Renal biopsy from affected individual FVI1 at 2 years (periodic acid-Schiff [PAS] in K and L; trichrome staining in M and N) showing severe tubulointerstitial lesions characterized by dedifferentiated and dilated tubules as well as atrophic tubules surrounded by marked thickening of the tubular basement membrane (arrow) and interstitial fibrosis with infiltrates (asterisks). Scale bar: 100 μm. The American Journal of Human Genetics 2012 90, 864-870DOI: (10.1016/j.ajhg.2012.03.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 IFT140 Organization, Protein Structure, and Mutations Identified in Homozygous and Compound-Heterozygous Individuals Affected with Skeletal Ciliopathies The American Journal of Human Genetics 2012 90, 864-870DOI: (10.1016/j.ajhg.2012.03.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Distribution of Wild-Type and Mutant Endogenous or Flag-Tagged IFT140 in Fibroblasts and RPE1 Cells (A) Aberrant distribution of Flag-tagged mutant IFT140 proteins in RPE1 cells. Cells were transfected with pCMV-IFT140-WT-Flag, pCMV-IFT140-Glu212Arg-Flag, pCMV-IFT140-Ile233Met-Flag, pCMV-IFT140-Tyr311Cys-Flag, and pCMV-IFT140-Glu664Lys-Flag plasmids, respectively. Flag-tagged proteins were stained with the use of rabbit anti-Flag (1:200, Sigma-Aldrich) and Alexa Fluor 555-conjugated anti-rabbit (1:200, Molecular Probes; red) primary and secondary antibodies, respectively. Basal bodies were stained with the use of mouse monoclonal anti-γ-tubulin (1:1000, Sigma-Aldrich) and Alexa Fluor 488-conjugated anti-mouse (1:200, Molecular Probes) primary and secondary antibodies, respectively. Images were recorded with a Leica SP5 confocal microsocope (Leica). Scale bars 5 μm. Wild-type (WT) IFT140 is clearly visible at the basal body (white arrow), whereas mutant proteins exhibit a significant cytoplasmic staining with decreased basal body labeling. The graph shows the percentage of transfected cells with localization of the Flag-tagged IFT140 protein at the basal body calculated from two independent experiments, and n > 100 cells for each transfection condition (∗∗∗: p < 0.001 calculated via Dunn's Multiple Comparison Test following the analysis of variance [ANOVA] test, GraphPad Prism Software). (B) Significantly decreased cilia abundance in serum-starved fibroblasts of MSS-affected individuals with IFT140 mutations compared to two controls (mean affected individuals versus mean controls: 55.10% versus 83.61% calculated from two independent experiments and n > 140 cells; ∗∗∗: p < .0001 calculated via the Fisher protected least significant difference [PLSD] test according to the significance of the Student's t test; StatView software version 5.0). Basal bodies were stained with the use of rabbit polyclonal anti-pericentrin (1:500, Abcam) and Alexa Fluor 488-conjugated goat anti-rabbit (1:1000, Sigma-Aldrich; green) primary and secondary antibodies, respectively. Axonemes were stained with the use of mouse monoclonal anti-acetylated alpha-tubulin (1:1000, Sigma-Aldrich) and Alexa Fluor 594 goat anti-mouse (1:1000, Molecular Probes; red) primary and secondary antibodies, respectively. Images were recorded with a Zeiss LSM700 microscope (Carl Zeiss S.A.S.). Scale bars 10 μm. (C) Distribution of IFT components in fibroblasts of MSS-affected individuals and controls. IFTs were stained with the use of IFT140 (1:100, goat polyclonal), IFT46 (1:200, rabbit polyclonal; gift of F. Mallin-Guerin), and IFT88 (1:100, rabbit polyclonal; gift of C. Desdouets) primary antibodies and Alexa Fluor 488-conjugated goat anti-rabbit or rabbit anti-goat (1:1000; green) secondary antibodies. Axonemes were stained as described previously. Nuclei were labeled with the use of DAPI (Southern Biotech). Images were recorded with a Zeiss LSM700 confocal microscope (Carl Zeiss S.A.S.). Scale bars 5 μm. Acetylated alpha-tubulin and IFT140 were evenly distributed along the axoneme in control, patient FII1, and patient FIV3 cells (Pearson's coefficients calculated via the ImageJ 1.42d JACoP software ≥ .80). Despite apparently normal expression and localization of IFT140, IFT46 and IFT88 were mislocalized in cilia of affected individuals FII1 and FIV1 (even distribution along the axoneme versus predominant staining at the base and the tip [white arrows] of cilia in control cells). The graphs show the percentage of cilia exhibiting both basal and apical staining in controls versus affected individuals (calculated from two independent experiments and n ≥ 40 cells for each cell line and each IFT, ∗∗∗: p < 0.0001 calculated with the Student's t test; StatView software version 5.0). Error bars represent SD. The American Journal of Human Genetics 2012 90, 864-870DOI: (10.1016/j.ajhg.2012.03.006) Copyright © 2012 The American Society of Human Genetics Terms and Conditions