REPORT Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans Ranad Shaheen, 1,13 Hanan E. Shamseldin, 1,13 Catrina M. Loucks, 2,13 Mohammed Zain Seidahmed, 4 Shinu Ansari, 1 Mohamed Ibrahim Khalil, 5 Nadya Al-Yacoub, 3 Erica E. Davis, 6 Natalie A. Mola, 6 Katarzyna Szymanska, 7 Warren Herridge, 7 Albert E. Chudley, 8 Bernard N. Chodirker, 8 Jeremy Schwartzentruber, 9 Jacek Majewski, 9 Nicholas Katsanis, 6 Coralie Poizat, 3 Colin A. Johnson, 7 Jillian Parboosingh, 2,10 Kym M. Boycott, 11 A. Micheil Innes, 2,10, * and Fowzan S. Alkuraya 1,12, * Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syn- drome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedge- hog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies. The centrosome is a nonmembranous cellular organelle composed of a pair of unequal centrioles embedded in an electron-dense matrix known as the pericentriolar matrix. 1 Centrosomes are best known for their role during mitosis, when they undergo duplication and migrate from their perinuclear location to opposite poles in the cell, where they organize the microtubules that are bundled as spindles. These spindles emanate from each centrosome and tether the chromosomes by their kinetochores, an essential requirement for normal alignment during metaphase and proper segrega- tion during anaphase. 2 However, centrosomes also play important regulatory roles for microtubules in nonmitotic cells; these include regulation of intracel- lular transport 3 and formation of the primary cilium through a series of highly orchestrated steps involv- ing the relocation of the centrosome to the cell surface and subsequent recruitment of key structural and functional proteins. 4 The primary cilium can function as a mechanosensor, but its role in signal transduction during development is increasingly recognized in view of the widespread developmental anomalies that accom- pany primary-cilium defects, collectively known as cilio- pathies. 5,6 Ciliopathies comprise a wide-range of phenotypes, consistent with the near ubiquitous presence of primary cilia in mammalian tissues. Over 60 genes have been asso- ciated with various ciliopathy phenotypes, and it has become increasingly clear with the plethora of reports that link apparently distinct clinical phenotypes to muta- tions in the same individual genes that these phenotypes represent a spectrum in which isolated retinal dystrophy or nephronophthisis (MIM 256100) represent the mild end and perinatal lethal Meckel-Gruber syndrome (MKS [MIM 249000]) with severe brain malformation, polydac- tyly, and multicystic and/or dysplastic kidneys represents the extreme end. 7–9 The subset of affected individuals who can be explained by mutations in recognized genes varies greatly. For example, primary driver mutations have been identified in the majority of individuals with the intermediate Bardet-Biedl ciliopathy (MIM 209900), 10 whereas for other ciliopathies, such as Joubert syndrome (JBTS [MIM 213300]) and MKS, additional genes remain to be identified. 11,12 In this report, we describe three fam- ilies affected by JBTS or a syndrome similar to MKS (Table 1) but not linked to any of the established genes and identify CSPP1 (MIM 611654) as another member of the genes asso- ciated with ciliopathy phenotypes in humans. 1 Department of Genetics, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia; 2 Department of Medical Genetics, University of Calgary, Alberta Children’s Hospital, Calgary, AB T3B 6A8, Canada; 3 Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; 4 Department of Pediatrics, Security Forces Hospital, Riyadh 11481, Saudi Arabia; 5 Department of Obstetrics and Gynecology, Security Forces Hospital, Riyadh 11481, Saudi Arabia; 6 Center for Human Disease Modeling, Duke University, Durham, NC 22710, USA; 7 Leeds Institute of Molec- ular Medicine, St. James’s University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK; 8 Department of Paediatrics and Child Health and Depart- ment of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3A 1R9, Canada; 9 McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G4, Canada; 10 Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada; 11 Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada; 12 Department of Anat- omy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia 13 These authors contributed equally to this work *Correspondence: micheil.innes@albertahealthservices.ca (A.M.I.), falkuraya@kfshrc.edu.sa (F.S.A.) http://dx.doi.org/10.1016/j.ajhg.2013.11.010. Ó2014 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 94, 1–7, January 2, 2014 1 Please cite this article in press as: Shaheen et al., Mutations in CSPP1, Encoding a Core Centrosomal Protein, Cause a Range of Ciliopathy Phenotypes in Humans, The American Journal of Human Genetics (2014), http://dx.doi.org/10.1016/j.ajhg.2013.11.010