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

Rama Rao Damerla, Cheng Cui, George C. Gabriel, Xiaoqin Liu, Branch Craige, Brian C. Gibbs, Richard Francis, You Li, Bishwanath Chatterjee, Jovenal T. San Agustin, Thibaut Eguether, Ramiah Subramanian, George B. Witman, Jacques L. Michaud, Gregory J. Pazour, Cecilia W. Lo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberddv137
Pages (from-to)3994-4005
Number of pages12
JournalHuman Molecular Genetics
Volume24
Issue number14
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

Fingerprint

Cilia
Glass
Cell Polarity
Fibroblasts
Stereocilia
Multiple Birth Offspring
Exome
Polydactyly
Pulmonary Atresia
Joubert syndrome 1
Ciliopathies
Mutation
Pulmonary Valve Stenosis
Congenital Heart Defects
Cochlea
Missense Mutation
Wound Healing
Cerebellum
Cell Movement
Cysts

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Novel Jbts17 mutant mouse model of joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies. / Damerla, Rama Rao; Cui, Cheng; Gabriel, George C.; Liu, Xiaoqin; Craige, Branch; Gibbs, Brian C.; Francis, Richard; Li, You; Chatterjee, Bishwanath; San Agustin, Jovenal T.; Eguether, Thibaut; Subramanian, Ramiah; Witman, George B.; Michaud, Jacques L.; Pazour, Gregory J.; Lo, Cecilia W.

In: Human Molecular Genetics, Vol. 24, No. 14, ddv137, 15.07.2015, p. 3994-4005.

Research output: Contribution to journalArticle

Damerla, RR, Cui, C, Gabriel, GC, Liu, X, Craige, B, Gibbs, BC, Francis, R, Li, Y, Chatterjee, B, San Agustin, JT, Eguether, T, Subramanian, R, Witman, GB, Michaud, JL, Pazour, GJ & Lo, CW 2015, 'Novel Jbts17 mutant mouse model of joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies', Human Molecular Genetics, vol. 24, no. 14, ddv137, pp. 3994-4005. https://doi.org/10.1093/hmg/ddv137
Damerla, Rama Rao ; Cui, Cheng ; Gabriel, George C. ; Liu, Xiaoqin ; Craige, Branch ; Gibbs, Brian C. ; Francis, Richard ; Li, You ; Chatterjee, Bishwanath ; San Agustin, Jovenal T. ; Eguether, Thibaut ; Subramanian, Ramiah ; Witman, George B. ; Michaud, Jacques L. ; Pazour, Gregory J. ; Lo, Cecilia W. / Novel Jbts17 mutant mouse model of joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies. In: Human Molecular Genetics. 2015 ; Vol. 24, No. 14. pp. 3994-4005.
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abstract = "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.",
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AU - Damerla, Rama Rao

AU - Cui, Cheng

AU - Gabriel, George C.

AU - Liu, Xiaoqin

AU - Craige, Branch

AU - Gibbs, Brian C.

AU - Francis, Richard

AU - Li, You

AU - Chatterjee, Bishwanath

AU - San Agustin, Jovenal T.

AU - Eguether, Thibaut

AU - Subramanian, Ramiah

AU - Witman, George B.

AU - Michaud, Jacques L.

AU - Pazour, Gregory J.

AU - Lo, Cecilia W.

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