Mutations in CSPP1 cause primary cilia abnormalities and joubert syndrome with or without Jeune asphyxiating thoracic dystrophy

Karina Tuz, Ruxandra Bachmann-Gagescu, Diana R. O'Day, Kiet Hua, Christine R. Isabella, Ian G. Phelps, Allan E. Stolarski, Brian O'Roak, Jennifer C. Dempsey, Charles Lourenco, Abdulrahman Alswaid, Carsten G. Bönnemann, Livija Medne, Sheela Nampoothiri, Zornitza Stark, Richard J. Leventer, Meral Topçu, Ali Cansu, Sujatha Jagadeesh, Stephen DoneGisele E. Ishak, Ian A. Glass, Jay Shendure, Stephan C F Neuhauss, Chad R. Haldeman-Englert, Dan Doherty, Russell J. Ferland

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)62-72
Number of pages11
JournalAmerican Journal of Human Genetics
Volume94
Issue number1
DOIs
StatePublished - Jan 2 2014

Fingerprint

Spindle Poles
Centrosome
Cilia
Mutation
Proteins
Zebrafish
Phenotype
Morpholinos
Joubert syndrome 1
Jeune syndrome
Cysts
Fibroblasts

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mutations in CSPP1 cause primary cilia abnormalities and joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. / Tuz, Karina; Bachmann-Gagescu, Ruxandra; O'Day, Diana R.; Hua, Kiet; Isabella, Christine R.; Phelps, Ian G.; Stolarski, Allan E.; O'Roak, Brian; Dempsey, Jennifer C.; Lourenco, Charles; Alswaid, Abdulrahman; Bönnemann, Carsten G.; Medne, Livija; Nampoothiri, Sheela; Stark, Zornitza; Leventer, Richard J.; Topçu, Meral; Cansu, Ali; Jagadeesh, Sujatha; Done, Stephen; Ishak, Gisele E.; Glass, Ian A.; Shendure, Jay; Neuhauss, Stephan C F; Haldeman-Englert, Chad R.; Doherty, Dan; Ferland, Russell J.

In: American Journal of Human Genetics, Vol. 94, No. 1, 02.01.2014, p. 62-72.

Research output: Contribution to journalArticle

Tuz, K, Bachmann-Gagescu, R, O'Day, DR, Hua, K, Isabella, CR, Phelps, IG, Stolarski, AE, O'Roak, B, Dempsey, JC, Lourenco, C, Alswaid, A, Bönnemann, CG, Medne, L, Nampoothiri, S, Stark, Z, Leventer, RJ, Topçu, M, Cansu, A, Jagadeesh, S, Done, S, Ishak, GE, Glass, IA, Shendure, J, Neuhauss, SCF, Haldeman-Englert, CR, Doherty, D & Ferland, RJ 2014, 'Mutations in CSPP1 cause primary cilia abnormalities and joubert syndrome with or without Jeune asphyxiating thoracic dystrophy', American Journal of Human Genetics, vol. 94, no. 1, pp. 62-72. https://doi.org/10.1016/j.ajhg.2013.11.019
Tuz, Karina ; Bachmann-Gagescu, Ruxandra ; O'Day, Diana R. ; Hua, Kiet ; Isabella, Christine R. ; Phelps, Ian G. ; Stolarski, Allan E. ; O'Roak, Brian ; Dempsey, Jennifer C. ; Lourenco, Charles ; Alswaid, Abdulrahman ; Bönnemann, Carsten G. ; Medne, Livija ; Nampoothiri, Sheela ; Stark, Zornitza ; Leventer, Richard J. ; Topçu, Meral ; Cansu, Ali ; Jagadeesh, Sujatha ; Done, Stephen ; Ishak, Gisele E. ; Glass, Ian A. ; Shendure, Jay ; Neuhauss, Stephan C F ; Haldeman-Englert, Chad R. ; Doherty, Dan ; Ferland, Russell J. / Mutations in CSPP1 cause primary cilia abnormalities and joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. In: American Journal of Human Genetics. 2014 ; Vol. 94, No. 1. pp. 62-72.
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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

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.

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.

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