Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish Julie C. Van De Weghe,

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Mutations in ARMC9, which Encodes a Basal Body Protein, Cause Joubert Syndrome in Humans and Ciliopathy Phenotypes in Zebrafish Julie C. Van De Weghe, Tamara D.S. Rusterholz, Brooke Latour, Megan E. Grout, Kimberly A. Aldinger, Ranad Shaheen, Jennifer C. Dempsey, Sateesh Maddirevula, Yong-Han H. Cheng, Ian G. Phelps, Matthias Gesemann, Himanshu Goel, Ohad S. Birk, Talal Alanzi, Rifaat Rawashdeh, Arif O. Khan, Michael J. Bamshad, Deborah A. Nickerson, Stephan C.F. Neuhauss, William B. Dobyns, Fowzan S. Alkuraya, Ronald Roepman, Ruxandra Bachmann-Gagescu, Dan Doherty The American Journal of Human Genetics Volume 101, Issue 1, Pages 23-36 (July 2017) DOI: 10.1016/j.ajhg.2017.05.010 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 ARMC9 Mutations Cause JS (A) The ARMC9 gene encodes a protein with an N-terminal LisH domain (green square), a coiled coil domain (yellow polygon), and a series of armadillo repeats (blue oval). Patient mutations are indicated by red arrows. (B–D) Confirmation of ARMC9 exon 14 deletion in UW116-3. No difference in the size or number of PCR products is observed between cDNA isolated from UW116-3 and two unaffected control cell lines using primers in exons 9 and 14 (C and D). Primers in exons 13 and 17 amplify a full-length product and a shorter product (bracket) in UW116-3, but only the full-length product in the two control lines. Sequencing genomic DNA amplified by primers flanking exon 14 reveals a 2,516 bp deletion with a 22 bp insertion (D). The American Journal of Human Genetics 2017 101, 23-36DOI: (10.1016/j.ajhg.2017.05.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Brain Imaging Findings in Individuals with ARMC9-Related Joubert Syndrome (A–C) MTS (A), inferior cerebellar dysplasia (white arrows in B), and superior cerebellar dysplasia (white arrow in C) in SA2-3. (D and E) MTS (D), posterior fossa cyst (asterisks in D and E), and ventriculomegaly (plus signs in E) in LR09-023. Note the single periventricular nodular heterotopia (black arrowhead in D). (F) Vermis hypoplasia and elevated roof of the 4th ventricle in SA2-3 (white arrow). (G) Cerebellar vermis hypoplasia and atrophy in UW132-3 (white arrow). (H) Kinked brainstem and cervicomedullary heterotopia in UW349-3 (white arrowhead). (I) Enlarged posterior fossa fluid collection (white asterisk) and rotated vermis (white arrowhead) in LR09-032. Axial T2-weighted images in (A)–(E); sagittal T1-weighted images in (F)–(I). The American Journal of Human Genetics 2017 101, 23-36DOI: (10.1016/j.ajhg.2017.05.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 ARMC9 Localization and ARMC9 Expression in Ciliated and Proliferating Cells (A) ARMC9 (green) localizes at the basal body (white arrow) and at the daughter centriole (white arrowhead) of the primary cilium in serum-starved hTERT RPE1 cells. The ciliary marker anti-RPGRIP1L (white) marks the ciliary transition zone and anti-acetylated α-tubulin (red) marks the ciliary axoneme. (B) ARMC9 (green) co-localizes with γ-tubulin (red) at the ciliary basal body in serum-starved hTERT RPE1 cells. Anti-RPGRIP1L marks distal to the basal body (white) and DAPI (blue) stains the nuclei. (C) ARMC9 expression in control human fibroblasts grown with serum (proliferating cells) and without serum (ciliated cells), assessed using qPCR with GAPDH as a reference gene. ARL13B is used as a positive control for a gene upregulated in ciliated cells. Error bars indicate standard deviation. The American Journal of Human Genetics 2017 101, 23-36DOI: (10.1016/j.ajhg.2017.05.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 armc9 Loss of Function in Zebrafish Leads to Typical Ciliopathy Phenotypes (A and B) Expression of armc9 in zebrafish adult brain (A) and retina (B) by in situ hybridization. Note the expression along ventricular surfaces in (A) and in all retinal layers, including the photoreceptor (PR) and the inner nuclear layer (INL) (B, B′). (C and D) Adult zebrafish harboring armc9 mutations display a curved body shape (D) compared to wild-type controls (C). (E and F) Scanning electron microscopy image of the ventricular surface demonstrates bundles of cilia in wild-type (E) but substantial reduction of cilia numbers in F0 armc9 fish (F). (G and H) Histological sections through adult zebrafish eyes of wild-type (G) and F0 armc9 mutants (H) showing a coloboma (arrow). (I and J) Higher-magnification images show the different retinal layers in wild-type fish (I) including the PRs and their long outer segments (OS, bracket) which represent highly specialized ciliary compartments. (J) Note the shortened OS in F0 armc9 mutants (bracket). Scale bars are 200 μm in (A) and (B), 50 μm in (B′), 5 mm in (C) and (D), 3 μm in (E) and (F), 250 μm in (G) and (H), and 50 μm in (I) and (J). Abbreviations are as follows: v, ventricle; PGZ, periventricular gray zone of optic tectum; Hv, ventral zone of periventricular hypothalamus; PR, photoreceptors; INL, inner nuclear layer. The American Journal of Human Genetics 2017 101, 23-36DOI: (10.1016/j.ajhg.2017.05.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions