TY - JOUR
T1 - Mutations in CSPP1 lead to classical joubert syndrome
AU - Akizu, Naiara
AU - Silhavy, Jennifer L.
AU - Rosti, Rasim Ozgur
AU - Scott, Eric
AU - Fenstermaker, Ali G.
AU - Schroth, Jana
AU - Zaki, Maha S.
AU - Sanchez, Henry
AU - Gupta, Neerja
AU - Kabra, Madhulika
AU - Kara, Majdi
AU - Ben-Omran, Tawfeg
AU - Rosti, Basak
AU - Guemez-Gamboa, Alicia
AU - Spencer, Emily
AU - Pan, Roger
AU - Cai, Na
AU - Abdellateef, Mostafa
AU - Gabriel, Stacey
AU - Halbritter, Jan
AU - Hildebrandt, Friedhelm
AU - Van Bokhoven, Hans
AU - Gunel, Murat
AU - Gleeson, Joseph G.
N1 - Funding Information:
We thank the affected children and their families for their invaluable contributions to this study, supported by National Institutes of Health grants R01NS041537, R01NS048453, R01NS052455, P01HD070494, and P30NS047101 (J.G.G.) and DK068306 (F.H.), the Howard Hughes Medical Institute (J.G.G. and F.H.), and the California Institute of Regenerative Medicine (N.A.). We thank the Broad Institute (U54HG003067 to E. Lander), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel) for sequencing support, T. Caspary for ARL13B antibody, and J. Santini at the University of California, San Diego Neuroscience Microscopy Core. CSPP1 has been designated as JBTS21 by the HUGO Gene Nomenclature Committee.
PY - 2014/1/2
Y1 - 2014/1/2
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2013.11.015
DO - 10.1016/j.ajhg.2013.11.015
M3 - Article
C2 - 24360807
AN - SCOPUS:84891834962
SN - 0002-9297
VL - 94
SP - 80
EP - 86
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -
