Mutations in CSPP1 lead to classical Joubert syndrome

Am J Hum Genet. 2014 Jan 2;94(1):80-6. doi: 10.1016/j.ajhg.2013.11.015.

Naiara Akizu ¹, Jennifer L Silhavy ¹, Rasim Ozgur Rosti ¹, Eric Scott ¹, Ali G Fenstermaker ¹, Jana Schroth ¹, Maha S Zaki ², Henry Sanchez ³, Neerja Gupta ⁴, Madhulika Kabra ⁴, Majdi Kara ⁵, Tawfeg Ben-Omran ⁶, Basak Rosti ¹, Alicia Guemez-Gamboa ¹, Emily Spencer ¹, Roger Pan ¹, Na Cai ¹, Mostafa Abdellateef ¹, Stacey Gabriel ⁷, Jan Halbritter ⁸, Friedhelm Hildebrandt ⁸, Hans van Bokhoven ⁹, Murat Gunel ¹⁰, Joseph G Gleeson ¹¹

Affiliations

1 Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
2 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
3 Pediatrics Department, Palo Alto Medical Foundation, Fremont, CA 94538, USA.
4 Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India.
5 Department of Pediatrics, Tripoli Children's Hospital, PO Box 2214, Tripoli, Libya.
6 Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.
7 The Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
8 Howard Hughes Medical Institute; Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
9 Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
10 Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
11 Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute. Electronic address: jogleeson@ucsd.edu.

PMID: 24360807 DOI: 10.1016/j.ajhg.2013.11.015

Abstract

Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of Other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.

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