Loss-of-Function Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with Central- Complex and Radial-Spoke Defects Esther Kott, Marie Legendre, Bruno.

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Loss-of-Function Mutations in RSPH1 Cause Primary Ciliary Dyskinesia with Central- Complex and Radial-Spoke Defects Esther Kott, Marie Legendre, Bruno Copin, Jean-François Papon, Florence Dastot-Le Moal, Guy Montantin, Philippe Duquesnoy, William Piterboth, Daniel Amram, Laurence Bassinet, Julie Beucher, Nicole Beydon, Eric Deneuville, Véronique Houdouin, Hubert Journel, Jocelyne Just, Nadia Nathan, Aline Tamalet, Nathalie Collot, Ludovic Jeanson, Morgane Le Gouez, Benoit Vallette, Anne-Marie Vojtek, Ralph Epaud, André Coste, Annick Clement, Bruno Housset, Bruno Louis, Estelle Escudier, Serge Amselem The American Journal of Human Genetics Volume 93, Issue 3, Pages 561-570 (September 2013) DOI: 10.1016/j.ajhg.2013.07.013 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 CC and RS Defects in Respiratory Cilia of Individuals with RSPH1 Mutations The electron micrographs of cross-sections of cilia from a control and ten individuals with identified biallelic RSPH1 mutations are shown. For each affected individual, two sections are shown: one with a normal configuration showing the presence of the CC and RSs (top) and the other with an abnormal axonemal configuration characterized by CC and RS abnormalities (bottom). The yellow flashes show the presence of normal CCs in the normal control and the affected individuals; RSs are encircled in yellow in the normal control and in cilia with CCs from affected individuals. The red flashes show CC defects (including the 8+1 pattern in DCP781) in affected individuals. Black scale bars represent 0.1 μm. The American Journal of Human Genetics 2013 93, 561-570DOI: (10.1016/j.ajhg.2013.07.013) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 RSPH1 Mutations and Their Impact at the Protein Level in Individuals with PCD (A) Exonic organization of the human RSPH1 cDNA, in which are shown the mutations for the ten families described in this study (top), and a domain-organization model of the corresponding protein (middle). The mutations’ impact at the protein level is shown (bottom). The nine exons are indicated by empty or hashed boxes depicting translated or untranslated sequences, respectively. According to the prediction tools provided by the NCBI and UniProt (see Web Resources), RSPH1 contains five MORN repeats, followed by a linker and a sixth MORN repeat. (B) A partial protein alignment of RSPH1 in different species shows the evolutionary conservation of the fourth MORN repeat, which contains the amino acid substitution identified in this study. The American Journal of Human Genetics 2013 93, 561-570DOI: (10.1016/j.ajhg.2013.07.013) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 RSPH1 Localizes to Cilia and Is Absent from Airway Epithelial Cells of DCP1064 (A–F) In airway epithelial cells of a healthy control (A–C) and the healthy father of DCP1064 (D–F), RSPH1 (green) localizes within cilia (red). (G–I) In cells from individual DCP1064, RSPH1 labeling is absent from cilia. Airway epithelial cells were examined after labeling with a rabbit RSPH1 polyclonal antibody (Sigma HPA017382, 1:100, 37°C, 1 hr) and a secondary goat anti-rabbit Alexa Fluor-488 (green) antibody (Invitrogen, A11034). For controls, we used an antibody directed against acetylated α-tubulin (mouse monoclonal [6-11B-1], Abcam ab24610, 1:700) for the visualization of microtubules revealed by a secondary goat anti-mouse Alexa Fluor-594 (red) antibody (Invitrogen, A11032). Nuclei were stained with DAPI (Sigma, 32670). White scale bars represent 10 μm. The American Journal of Human Genetics 2013 93, 561-570DOI: (10.1016/j.ajhg.2013.07.013) Copyright © 2013 The American Society of Human Genetics Terms and Conditions