Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Ramsbottom, Simon A.; Thelwall, Peter E.; Wood, Katrina; Clowry, Gavin J.; Devlin, Laura A; Silbermann, Flora; Spiewak, H.L.; Shril, Shirlee; Molinari, Elisa; Hildebrandt, Friedhelm; Gunay‐Aygun, Meral; Saunier, Sophie; Cordell, Heather J.; Miles, Colin

doi:10.1073/pnas.1912602117

Cited by 23 publications

(18 citation statements)

References 36 publications

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“…We noted that while 3 dpf MZcep290-/-mutants initially show an axis curvature phenotype similar to the morpholino knockdown phenotype, axis curvature recovered suggesting the axis phenotype was transiently and partially suppressed. To further explore the possibility of phenotype suppression in MZcep290 -/-mutants, we assayed for nonsense-associated altered splicing of mutated exons as has been reported to account for varying expressivity in CEP290 patients (Barny et al, 2018;Littink et al, 2010;Ramsbottom et al, 2020). RT-PCR analysis of mutant and wild type cep290 mRNA exon structure using primers designed for ten exons flanking the mutated exon 16 (Fig 4C ) did not detect changes in amplicon sizes between wild type and mutants, suggesting that exon skipping does not account for differing degrees of cep290 deficiency phenotype severity.…”

Section: Cep290 Mutant Expressivity Is Not Due To Exon Skipping or Nonsense Mediated Decay Mechanismsmentioning

confidence: 99%

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Cárdenas-Rodríguez

Austin‐Tse

Bergboer

et al. 2021

Journal of Cell Science

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Mutations in CEP290, a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b, and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human JBTS CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies.

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Section: Cep290 Mutant Expressivity Is Not Due To Exon Skipping or Nonsense Mediated Decay Mechanismsmentioning

confidence: 99%

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Cárdenas-Rodríguez

Austin‐Tse

Bergboer

et al. 2021

Journal of Cell Science

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“…It is important to note that the type of genetic defect in animal models (knockout/loss of function or missense mutations) and the genetic background strain with associated genetic modifiers impact the severity of the phenotype and the utility of the model for human disease, as was demonstrated in mouse models of Cep290-associated ciliopathies (Ramsbottom et al, 2015(Ramsbottom et al, , 2020. Patient-derived in vitro systems, for example urinary renal epithelial cells (URECs), kidney tubuloids and organoids, could partly solve these issues (Schutgens et al, 2019;Steichen et al, 2020).…”

Section: Available Model Systems Animal Modelsmentioning

confidence: 99%

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Stokman

Saunier

Benmerah

2021

Front. Cell Dev. Biol.

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Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

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“…Indeed, additional signaling pathways are linked to cilia including others known to be important in cell proliferation and axon guidance. Loss of either of the JSRD-linked genes Ahi1 or Cep290 in mouse leads to a small cerebellar vermis due to aberrant Wnt signaling (Lancaster et al 2011; Ramsbottom et al 2020). JSRD-causing mutations in Znf423 are linked to defects in Wnt, BMP and retinoic acid signaling (Hata et al 2000, Huang et al 2009, Casoni et al 2020, Deshpande et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

Suciu

Long

Caspary

2021

Preprint

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Patients with the ciliopathy Joubert syndrome present with physical anomalies, intellectual disability, and are diagnosed by the hindbrain “molar tooth sign” malformation. This radiological abnormality results from a combination of hypoplasia of the cerebellar vermis and inappropriate targeting of the white matter tracts of the superior cerebellar peduncles, which create a deepened interpeduncular fossa. ARL13B is a cilia-enriched regulatory GTPase established to regulate cell fate, cell proliferation and axon guidance through vertebrate Hedgehog signaling. In patients, point mutations in ARL13B cause Joubert syndrome. In order to understand the etiology of the molar tooth sign, we used mouse models to investigate the role of ARL13B during cerebellar development. We found ARL13B regulates superior cerebellar peduncle targeting and these fiber tracts require Hedgehog signaling for proper guidance. However, in mouse the Joubert-causing R79Q mutation in ARL13B does not disrupt Hedgehog signaling nor does it impact tract targeting. We found a small cerebellar vermis in mice lacking ARL13B function but no cerebellar vermis hypoplasia in mice expressing the Joubert-causing R79Q mutation. Additionally, mice expressing a cilia-excluded variant of ARL13B that transduces Hedgehog normally, showed normal tract targeting and vermis size. Taken together, our data indicate that ARL13B is critical for superior cerebellar peduncle targeting, likely via Hedgehog signaling, as well as control of cerebellar vermis size. Thus, our work highlights the complexity of ARL13B in molar tooth sign etiology.Summary statementJoubert syndrome is diagnosed by the hindbrain “molar tooth sign” malformation. Using mouse models, we show loss of the ciliary GTPase ARL13B, mutations in which lead to Joubert syndrome, result in two features of the molar tooth sign: hypoplasia of the cerebellar vermis and inappropriate targeting of the superior cerebellar peduncles. Furthermore, we demonstrate that loss of vertebrate Hedgehog signaling may be the underlying disrupted mechanism as we extend its role in axon guidance to the superior cerebellar peduncles.

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Mouse genetics reveals Barttin as a genetic modifier of Joubert syndrome

Cited by 23 publications

References 36 publications

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Genetic compensation for cilia defects in cep290 mutants by upregulation of cilia-associated small GTPases

Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Smoothened and ARL13B are critical in mouse for superior cerebellar peduncle targeting

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