TY - JOUR
T1 - Mutations in CSPP1 cause primary cilia abnormalities and joubert syndrome with or without Jeune asphyxiating thoracic dystrophy
AU - Tuz, Karina
AU - Bachmann-Gagescu, Ruxandra
AU - O'Day, Diana R.
AU - Hua, Kiet
AU - Isabella, Christine R.
AU - Phelps, Ian G.
AU - Stolarski, Allan E.
AU - O'Roak, Brian J.
AU - Dempsey, Jennifer C.
AU - Lourenco, Charles
AU - Alswaid, Abdulrahman
AU - Bönnemann, Carsten G.
AU - Medne, Livija
AU - Nampoothiri, Sheela
AU - Stark, Zornitza
AU - Leventer, Richard J.
AU - Topçu, Meral
AU - Cansu, Ali
AU - Jagadeesh, Sujatha
AU - Done, Stephen
AU - Ishak, Gisele E.
AU - Glass, Ian A.
AU - Shendure, Jay
AU - Neuhauss, Stephan C.F.
AU - Haldeman-Englert, Chad R.
AU - Doherty, Dan
AU - Ferland, Russell J.
N1 - Funding Information:
Our deepest thanks go to all of the individuals with Joubert syndrome and their families. This work was supported in part by the Swiss National Science Foundation (PZ00P3_142404 to R.B.-G.), the March of Dimes Foundation (5-FY09-29 to R.J.F.), and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS064077 and University of Washington Intellectual and Developmental Disabilities Research Center Genetics Core P30HD002274 to D.D. and R01NS064283 to R.J.F.). We also acknowledge private donations from the families of children with Joubert syndrome.
PY - 2014/1/2
Y1 - 2014/1/2
N2 - Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.
AB - Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.
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U2 - 10.1016/j.ajhg.2013.11.019
DO - 10.1016/j.ajhg.2013.11.019
M3 - Article
C2 - 24360808
AN - SCOPUS:84891833623
SN - 0002-9297
VL - 94
SP - 62
EP - 72
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -