Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies

Hum Mol Genet. 2015 Jul 15;24(14):3994-4005. doi: 10.1093/hmg/ddv137. Epub 2015 Apr 15.


Recent studies identified a previously uncharacterized gene C5ORF42 (JBTS17) as a major cause of Joubert syndrome (JBTS), a ciliopathy associated with cerebellar abnormalities and other birth defects. Here we report the first Jbts17 mutant mouse model, Heart Under Glass (Hug), recovered from a forward genetic screen. Exome sequencing identified Hug as a S235P missense mutation in the mouse homolog of JBTS17 (2410089e03rik). Hug mutants exhibit multiple birth defects typical of ciliopathies, including skeletal dysplasia, polydactyly, craniofacial anomalies, kidney cysts and eye defects. Some Hug mutants exhibit congenital heart defects ranging from mild pulmonary stenosis to severe pulmonary atresia. Immunostaining showed JBTS17 is localized in the cilia transition zone. Fibroblasts from Hug mutant mice and a JBTS patient with a JBTS17 mutation showed ciliogenesis defects. Significantly, Hug mutant fibroblasts showed loss of not only JBTS17, but also NPHP1 and CEP290 from the cilia transition zone. Hug mutants exhibited reduced ciliation in the cerebellum. This was associated with reduction in cerebellar foliation. Using a fibroblast wound-healing assay, we showed Hug mutant cells cannot establish cell polarity required for directional cell migration. However, stereocilia patterning was grossly normal in the cochlea, indicating planar cell polarity is not markedly affected. Overall, we showed the JBTS pathophysiology is replicated in the Hug mutant mice harboring a Jbts17 mutation. Our findings demonstrate JBTS17 is a cilia transition zone component that acts upstream of other Joubert syndrome associated transition zone proteins NPHP1 and CEP290, indicating its importance in the pathogenesis of Joubert syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics
  • Abnormalities, Multiple / pathology
  • Adaptor Proteins, Signal Transducing
  • Amino Acid Sequence
  • Animals
  • Antigens, Neoplasm
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Polarity
  • Cells, Cultured
  • Cerebellar Diseases / genetics*
  • Cerebellar Diseases / pathology
  • Cerebellum / abnormalities*
  • Cerebellum / pathology
  • Cilia
  • Cytoskeletal Proteins
  • Disease Models, Animal
  • Eye Abnormalities / genetics
  • Eye Abnormalities / pathology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Kidney Diseases, Cystic / genetics
  • Kidney Diseases, Cystic / pathology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Confocal
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pregnancy
  • Protein Transport / genetics
  • Retina / abnormalities*
  • Retina / pathology


  • Adaptor Proteins, Signal Transducing
  • Antigens, Neoplasm
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cep290 protein, mouse
  • Cytoskeletal Proteins
  • Jbts17 protein, mouse
  • Membrane Proteins
  • Nphp1 protein, mouse
  • Nuclear Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis