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Am J Hum Genet DOI:10.1016/j.ajhg.2013.11.015

Mutations in CSPP1 lead to classical Joubert syndrome.

Publication TypeJournal Article
Year of Publication2014
AuthorsAkizu, N, Silhavy, JL, Rosti, ROzgur, Scott, E, Fenstermaker, AG, Schroth, J, Zaki, MS, Sanchez, H, Gupta, N, Kabra, M, Kara, M, Ben-Omran, T, Rosti, B, Guemez-Gamboa, A, Spencer, E, Pan, R, Cai, N, Abdellateef, M, Gabriel, S, Halbritter, J, Hildebrandt, F, van Bokhoven, H, Gunel, M, Gleeson, JG
JournalAm J Hum Genet
Volume94
Issue1
Pages80-6
Date Published2014 Jan 02
ISSN1537-6605
KeywordsAbnormalities, Multiple, Brain, Cell Cycle Proteins, Centrosome, Cerebellar Diseases, Cerebellum, Cilia, Cohort Studies, Eye Abnormalities, Fibroblasts, Gene Deletion, Humans, Image Processing, Computer-Assisted, Kidney Diseases, Cystic, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Retina
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0002-9297(13)00530-2
DOI10.1016/j.ajhg.2013.11.015
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24360807?dopt=Abstract

Alternate JournalAm. J. Hum. Genet.
PubMed ID24360807
PubMed Central IDPMC3882909
Grant ListDK068306 / DK / NIDDK NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
P30NS047101 / NS / NINDS NIH HHS / United States
R01NS048453 / NS / NINDS NIH HHS / United States
P30 NS047101 / NS / NINDS NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
R01 NS041537 / NS / NINDS NIH HHS / United States
R01 NS048453 / NS / NINDS NIH HHS / United States
U54HG006504 / HG / NHGRI NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
R01 NS052455 / NS / NINDS NIH HHS / United States
P01 HD070494 / HD / NICHD NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P01HD070494 / HD / NICHD NIH HHS / United States
R01NS041537 / NS / NINDS NIH HHS / United States
R01NS052455 / NS / NINDS NIH HHS / United States