Defective ciliogenesis in INPP5E-related Joubert syndrome

Isabel Hardee, Ariane Soldatos, Mariska Davids, Thierry Vilboux, Camilo Toro, Karen L. David, Carlos R. Ferreira, Michele Nehrebecky, Joseph Snow, Audrey Thurm, Theo Heller, Ellen F. Macnamara, Meral Gunay-Aygun, Wadih M. Zein, William A. Gahl, May Christine V. Malicdan

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Joubert syndrome is a neurodevelopmental disorder, characterized by malformation of the mid and hindbrain leading to the pathognomonic molar tooth appearance of the brainstem and cerebellum on axial MRI. Core clinical manifestations include hypotonia, tachypnea/apnea, ataxia, ocular motor apraxia, and developmental delay of varying degrees. In addition, a subset of patients has retinal dystrophy, chorioretinal colobomas, hepatorenal fibrocystic disease, and polydactyly. Joubert syndrome exhibits genetic heterogeneity, with mutations identified in more than 30 genes, including INPP5E, a gene encoding inositol polyphosphate 5-phosphatase E, which is important in the development and stability of the primary cilium. Here, we report the detailed clinical phenotypes of two sisters with a novel homozygous variant in INPP5E (NM_019892.4: c.1565G>C, NP_063945.2: p.Gly552Ala), expanding the phenotype associated with Joubert syndrome type 1. Expression studies using patient-derived fibroblasts showed changes in mRNA and protein levels. Analysis of fibroblasts from patients revealed that a significant number of cells had shorter or no cilia, indicating defects in ciliogenesis, and cilia maintenance.

Original languageEnglish (US)
Pages (from-to)3231-3237
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Issue number12
StatePublished - Dec 2017


  • INPP5E
  • Joubert syndrome
  • ciliopathy
  • molar-tooth sign
  • rare disorders

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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