Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans Ranad Shaheen, Hanan E. Shamseldin, Catrina M.

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Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans Ranad Shaheen, Hanan E. Shamseldin, Catrina M. Loucks, Mohammed Zain Seidahmed, Shinu Ansari, Mohamed Ibrahim Khalil, Nadya Al-Yacoub, Erica E. Davis, Natalie A. Mola, Katarzyna Szymanska, Warren Herridge, Albert E. Chudley, Bernard N. Chodirker, Jeremy Schwartzentruber, Jacek Majewski, Nicholas Katsanis, Coralie Poizat, Colin A. Johnson, Jillian Parboosingh, Kym M. Boycott, A. Micheil Innes, Fowzan S. Alkuraya The American Journal of Human Genetics Volume 94, Issue 1, Pages 73-79 (January 2014) DOI: 10.1016/j.ajhg.2013.11.010 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Ciliopathy Phenotypes in Three Consanguineous Families (A) Pedigrees of the three study families are shown. The proband is indicated in each pedigree by an arrow, and asterisks denote individuals whose DNA was available for analysis. Please note that the degree of consanguinity between I:1 and I:2 in families 2 and 3 is uncertain but that the average relationship is first cousins once removed.13 (B and C) Prenatal sonographic images of V:1 in family 1 show echogenic kidneys (B) and occipital encephalocele (C). (D and E) Prenatal sonographic images of V:3 in family 1 show echogenic kidneys (D) and occipital encephalocele (E). (F) A skeletal survey of V:3 in family 1 shows a severe skull defect. (G and H) A side view (G) and top view (H) of MRI of the family 2 proband show typical cerebellar involvement of JBTS. The American Journal of Human Genetics 2014 94, 73-79DOI: (10.1016/j.ajhg.2013.11.010) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of Two Homozygous Truncating Mutations in CSPP1 Schematic of the CSPP and CSPP-L isoforms. The locations of the two truncating CSPP1 alterations identified in the three families are indicated along with the CSPP1 sequence chromatograms. Red boxes indicate potential coiled-coil regions. The American Journal of Human Genetics 2014 94, 73-79DOI: (10.1016/j.ajhg.2013.11.010) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 CSPP1-Related Ciliopathy Is Associated with Impaired SHH Signaling and Ciliogenesis Defects (A) mRNA expression of GLI1 was markedly lower in fibroblasts from V:3 in family 1 than in control fibroblasts in response to SAG stimulation of 100 nM for 18 hr (p < 0.0084 on the basis of three independent experiments each performed in triplicate). Error bars represent the SEM. (B and C) Immunofluorescence images of serum-starved fibroblasts from the affected individual in family 3 (B) and control fibroblasts (C) stained for the ciliary marker acetylated α-tubulin (Sigma-Aldrich) (green) and DNA (blue). Compared to controls, fibroblasts from V:3 in family 1 showed a marked ciliogenesis defect at 40× magnification. Scale bars represent 50 μm. The American Journal of Human Genetics 2014 94, 73-79DOI: (10.1016/j.ajhg.2013.11.010) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 Abnormal Localization of RPGRIP1L in Cells with a CSPP1 Mutation Immunofluorescence images of serum-starved fibroblasts from the affected individual in family 3 (A) and control fibroblasts (B) stained for the ciliary marker acetylated α-tubulin (green), RPGRIP1L (Proteintech, catalog no. 55160-1-AP) (red), and DNA (blue). (A) The localization of RPGRIP1L at the basal body was lost in mutant fibroblasts. (B) RPGRIP1L localized normally at the basal body of the cilia in control fibroblasts. The American Journal of Human Genetics 2014 94, 73-79DOI: (10.1016/j.ajhg.2013.11.010) Copyright © 2014 The American Society of Human Genetics Terms and Conditions