ZFIN ID: ZDB-PUB-140220-20
Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy
Tuz, K., Bachmann-Gagescu, R., O'Day, D.R., Hua, K., Isabella, C.R., Phelps, I.G., Stolarski, A.E., O'Roak, B.J., Dempsey, J.C., Lourenco, C., Alswaid, A., Bönnemann, C.G., Medne, L., Nampoothiri, S., Stark, Z., Leventer, R.J., Topçu, M., Cansu, A., Jagadeesh, S., Done, S., Ishak, G.E., Glass, I.A., Shendure, J., Neuhauss, S.C., Haldeman-Englert, C.R., Doherty, D., and Ferland, R.J.
Date: 2014
Source: American journal of human genetics   94(1): 62-72 (Journal)
Registered Authors: Bachmann-Gagescu, Ruxandra, Neuhauss, Stephan, Phelps, Ian
Keywords: none
MeSH Terms:
  • Abnormalities, Multiple
  • Adolescent
  • Animals
  • Cell Cycle Proteins/genetics*
  • Cerebellar Diseases/genetics*
  • Cerebellum/abnormalities
  • Child
  • Child, Preschool
  • Cilia/genetics*
  • Cilia/pathology
  • Ellis-Van Creveld Syndrome/genetics*
  • Exons
  • Eye Abnormalities/genetics*
  • Female
  • Fibroblasts/cytology
  • Fibroblasts/metabolism
  • Gene Knockdown Techniques
  • Humans
  • Infant
  • Kidney Diseases, Cystic/genetics*
  • Male
  • Microtubule-Associated Proteins/genetics*
  • Mutation*
  • Phenotype
  • Retina/abnormalities*
  • Sequence Analysis, DNA
  • Young Adult
  • Zebrafish/genetics
PubMed: 24360808 Full text @ Am. J. Hum. Genet.
FIGURES
ABSTRACT

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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