Jan Halbritter, Albane A. Bizet, Miriam Schmidts, Jonathan D

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Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans Jan Halbritter, Albane A. Bizet, Miriam Schmidts, Jonathan D. Porath, Daniela A. Braun, Heon Yung Gee, Aideen M. McInerney-Leo, Pauline Krug, Emilie Filhol, Erica E. Davis, Rannar Airik, Peter G. Czarnecki, Anna M. Lehman, Peter Trnka, Patrick Nitschké, Christine Bole-Feysot, Markus Schueler, Bertrand Knebelmann, Stéphane Burtey, Attila J. Szabó, Kálmán Tory, Paul J. Leo, Brooke Gardiner, Fiona A. McKenzie, Andreas Zankl, Matthew A. Brown, Jane L. Hartley, Eamonn R. Maher, Chunmei Li, Michel R. Leroux, Peter J. Scambler, Shing H. Zhan, Steven J. Jones, Hülya Kayserili, Beyhan Tuysuz, Khemchand N. Moorani, Alexandru Constantinescu, Ian D. Krantz, Bernard S. Kaplan, Jagesh V. Shah, Toby W. Hurd, Dan Doherty, Nicholas Katsanis, Emma L. Duncan, Edgar A. Otto, Philip L. Beales, Hannah M. Mitchison, Sophie Saunier, Friedhelm Hildebrandt The American Journal of Human Genetics Volume 93, Issue 5, Pages 915-925 (November 2013) DOI: 10.1016/j.ajhg.2013.09.012 Copyright © 2013 The Authors Terms and Conditions

Figure 1 Clinical Characteristics of Individuals with Recessive Mutations in IFT172 (A) A chest X-ray of individual A3215-21 shows a narrowed, bell-shaped thorax and short ribs. Note the tracheostomy for ventilation. (B) A hip X-ray of individual UCL-87 demonstrates a trident acetabular roof with spurs (white arrowheads). (C) Postaxial polydactyly of the feet in individual UCL-87. (D) A chest X-ray of individual UCL-107 shows a narrowed, bell-shaped thorax. (E) Obesity and short stature of individual NPH2218 at 10 years of age. (F) Renal histology of individual NPH2218 exhibits dilated tubules, disruption of the tubular basement membrane, and extensive interstitial fibrosis. (G) A hand X-ray of individual A3037-21 shows brachydactyly with cone-shaped epiphysis of the middle phalanges. (H) A babygram of individual SKDP-165.3 shows a turricephaly-like skull shape, absent nasal bone, postaxial tetramelic hexadactyly, shortened and curved long bones, short ribs, mild platyspondyly, and spur-like projections of the acetabular roof. (I) A trident acetabular roof with spurs (white arrowheads) in individual UCL-107. (J) Cranial MRI depicts partial agenesis of the cerebellar vermis in individual NPH2218. (K) Brachydactyly of individual NPH2218. (L) Narrow thorax of individual UCL-107. The American Journal of Human Genetics 2013 93, 915-925DOI: (10.1016/j.ajhg.2013.09.012) Copyright © 2013 The Authors Terms and Conditions

Figure 2 Biallelic IFT172 Mutations, Deduced Impact at Protein Level, and Subcellular Localization of WT IFT172 (A) Exon structure of human IFT172 cDNA. The positions of the start codon (ATG) and stop codon (TGA) are indicated. (B) Domain structure of IFT172, which contains 9 WD-40 repeats (WD), located N-terminal to 14 tetratricopeptide repeats (TPR) and 1 LIM domain. For the mutations detected, black arrows indicate positions in relation to exons and protein domains. Family numbers are underlined. Abbreviations are as follows: H, homozygous; and h, heterozygous. IFT172 animal mutants wim (mouse, p.Leu1564Pro) and fla11 (C. reinhardtii, p.Leu1615Pro) are indicated by red arrows. Note the proximity of the detected missense changes p.Leu1536Pro and p.Arg1544Cys to the wim locus at position Leu1564. (C) A partial protein alignment of IFT172 shows evolutionary conservation of the identified missense changes (p.Arg296Trp, p.Ile411Asn, p.Leu1536Pro, p.Arg1544Cys, and p.Cys1727Arg). (D) Antibody staining (polyclonal rabbit antibody, Abcam, 1:100) of WT IFT172 in human control fibroblasts shows axonemal and pericentriolar localization in comparison to acetylated tubulin (anti-acetylated alpha tubulin, mouse monoclonal antibody, Abcam, 1:1000). (E and F) Localization of human WT IFT172 constructs, once with an N-terminal GFP tag (E) and once with a C-terminal GFP tag (F), after transfection of a 48 hr serum-starved NIH 3T3 cell line. Immunofluorescence on a confocal microscope (Zeiss, LSM 720) confirmed axonemal localization with enrichment at the ciliary base upon overexpression. The American Journal of Human Genetics 2013 93, 915-925DOI: (10.1016/j.ajhg.2013.09.012) Copyright © 2013 The Authors Terms and Conditions

Figure 3 Alteration of Ciliogenesis and Ciliary Composition in Human Mutant Fibroblasts Control and mutant fibroblasts from individuals NPH2161, A2052-21, and NPH2218 were starved for 48 hr for inducing ciliogenesis and were fixed with MetOH. (A) Staining of ARL13B (polyclonal rabbit antibody, Proteintech; 1:400), quantification of ciliated cells, and measurement of cilia length with the use of Lucia G on Nikon DXM 1200 Software. Compared to controls, mutant fibroblasts displayed elongated cilia. The scale bar represents 10 μm. (B) Staining of acetylated-tubulin (mouse monoclonal antibody, Sigma Aldrich; 1:10,000), γ-tubulin (goat polyclonal antibody, Santa Cruz; 1:200), and IFT140 (polyclonal rabbit antibody, Proteintech; 1:100) showed a decrease in ciliary and an increase in basal body IFT140 staining intensity in mutant fibroblasts compared to controls. (C) Staining of adenylyl cyclase III (ACIII, rabbit polyclonal antibody, Santa Cruz; 1:100) showed a decrease in ciliary ACIII-staining intensity in mutant fibroblasts compared to controls. Images in (B) and (C) were recorded with a Leica SP8 confocal microscope and analyzed with ImageJ. All graphs show the mean ± SEM of at least three independent experiments. “ns” stands for not significant. ∗p < 0.05, ∗∗p < 0.01, and ∗∗∗p < 0.001 were calculated via Dunn’s Multiple Comparison Test after the analysis of variance ANOVA test. The American Journal of Human Genetics 2013 93, 915-925DOI: (10.1016/j.ajhg.2013.09.012) Copyright © 2013 The Authors Terms and Conditions

Figure 4 Knockdown of ift172 and ift80 and Genetic Epistasis between ift172 and ift80 in Zebrafish (A–C) When compared to the control (A), both ift172 (B) and ift80 (C) morphants displayed similar ciliopathy phenotypes, including ventral body-axis curvature (first row), formation of renal cysts (red arrows, second row), and cartilage defects with hypoplasia of the Meckel’s cartilage (mc) and widening of ceratohyal angle (cha), as shown by Alcian-blue staining (third and fourth row). (D–E) Zebrafish injected with subphenotypic doses of either ift172 (D) or ift80 (E) MO appeared no different than the control (A). (F) Similar to a full dose of each MO alone, combined injection of subphenotypic doses of ift172 MO and subphenotypic doses of ift80 MO resulted in body-axis curvature, formation of renal cysts, and cartilage defects. The American Journal of Human Genetics 2013 93, 915-925DOI: (10.1016/j.ajhg.2013.09.012) Copyright © 2013 The Authors Terms and Conditions