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

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.

Cilia and Ciliopathies in Congenital Heart Disease

“…On the flip side, there is undoubtedly ascertainment bias in our screen in the recovery of mutations in ciliopathy genes that specifically can cause CHD. That different ciliopathy mutations may have varying levels of penetrance for CHD phenotypes is suggested by observations of our mutant Hug (Damerla et al 2015). This mutant has a mutation in Jbts17, a gene encoding a cilia transition zone protein known to cause JBTS (Srour et al 2012).…”

“…2) (Li et al 2015). The cilia genes recovered included proteins localized in the cilia transition zone, basal body/centrosome, ciliary axoneme, and also multiprotein complexes in the cytoplasm required for cilia assembly (Fig.…”

“…Hug mutants show cerebellar defects expected for JBTS and they also can show CHD comprising of pulmonary atresia. However, the CHD phenotype is incomplete in penetrance, as some Hug mutants show no heart defects (Damerla et al 2015). These observations suggest that different mutations in the same ciliopathy gene may generate different phenotypic outcome and this perhaps can be further modified by the genetic background of the individual.…”

Primary Cilia and Mammalian Hedgehog Signaling

“…The CPLANE protein complex is located at the basal body and includes downstream mediators of planar cell polarity in Drosophila , Fuzzy , Inturned and Fritz ( Wdpcp ) and Jbts17 , a gene responsible for Joubert syndrome in humans (Damerla et al, 2015; Toriyama et al, 2016). The CPLANE complex is required for efficient ciliogenesis as it functions to recruit IFT-A proteins to the cilium RSG1, a small GTPase that appears to be a peripheral member of the CPLANE complex.…”

Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis

“…18 JBTS17 localization to the ciliary base was also observed in Xenopus laevis. 2 JBTS17 was also identified as a transition zone component in mouse embryonic fibroblasts.…”