Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior Loken syndrome

Helou, Juliana; Otto, Edgar A.; Attanasio, Massimo; Allen, Susan J.; Parisi, Melissa A.; Glass, Ian A.; Utsch, Boris; Hashmi, Seema; Fazzi, Elisa; Omran, Heymut; O’Toole, John F.; Sayer, John A.; Hildebrandt, Friedhelm

doi:10.1136/jmg.2007.052027

Cited by 95 publications

(79 citation statements)

References 31 publications

(40 reference statements)

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“…On the surface, the association between ARL13B and JS is consistent with the hypothesis that Joubert syndrome and related disorders (JSRD) are ciliopathy disorders, or diseases caused by ciliary defects (Bielas et al, 2009;Cantagrel et al, 2008;Castori et al, 2005;Dixon-Salazar et al, 2004;Gleeson et al, 2004;Gorden et al, 2008;Harris, 2007;Helou et al, 2007;Jacoby et al, 2009;Sharma et al, 2008;Utsch et al, 2006;Wolf et al, 2007). However, phenotypical analysis of patients with ARL13B mutations and sequence analysis of the ARL13B gene in patients with non-classical forms of JS seem to suggest that mutations in ARL13B are restricted to the classical form of JS, with symptoms predominantly limited to brain structure and function (Cantagrel et al, 2008).…”

Section: Introductionsupporting

confidence: 55%

“…The 'molar tooth sign' (MTS) in brain MRI scans resulting from structural abnormalities in the cerebellar vermis is a hallmark of classical JS (Gleeson et al, 2004;Harris, 2007;Sharma et al, 2008). As MTS can be found in patients with additional symptoms associated with ciliary defects, it is thought that ciliary defects might be the underlying mechanism of JSRD defects (Cantagrel et al, 2008;Castori et al, 2005;Dixon-Salazar et al, 2004;Gleeson et al, 2004;Gorden et al, 2008;Harris, 2007;Helou et al, 2007;Sharma et al, 2008;Utsch et al, 2006;Wolf et al, 2007). The findings that mutations in ARL13B are associated with JS and that Arl13b is required for cilia formation support this model.…”

Section: Discussionmentioning

confidence: 99%

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Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

2009

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arl13b was initially cloned as the novel cystic kidney gene scorpion (sco) in zebrafish and was shown to be required for cilia formation in the kidney duct. In mouse, a null mutant of Arl13b shows abnormal ultrastructure of the cilium and defective sonic hedgehog (Shh) signaling. Importantly, a recent study linked mutations in ARL13B to a classical form of Joubert syndrome (JS), an autosomal recessive disorder characterized by a distinctive cerebellar malformation. In this study, we analyzed the zebrafish arl13b (sco) mutant and gene products in detail. We first demonstrate that Arl13b is a protein that is highly enriched in the cilium and is required for cilia formation in multiple organs in zebrafish, and that knockdown of arl13b leads to multiple cilia-associated phenotypes. We additionally show that multiple regions of Arl13b are required for its localization to the cilium. By means of rescuing experiments with a series of deletion and point mutants, we further demonstrate that the ciliary localization is crucial for the in vivo function of Arl13b. Together, these results strongly support the hypothesis that JS-related disease (JSRD) is a ciliopathy, or a disease caused by ciliary defects, and that Arl13b functions mainly through the cilium.

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Section: Introductionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

2009

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“…A recent selective screen of 13 LCA genes in 60 affected subjects revealed a striking 43% of the mutant alleles in Cep290 (24), suggesting a significant contribution of this gene to retinal disease manifestation. In addition, mutations in Cep290 produce varying clinical outcomes of JBTS (25)(26)(27), MKS (28)(29)(30), and BBS (31). Cep290 has been implicated in ciliogenesis (32,33), which requires docking of the basal body to the plasma membrane and assembly of the BBSome (15) and chaperonin complexes (17).…”

Section: Introductionmentioning

confidence: 99%

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

Rachel¹,

May-Simera²,

Veleri³

et al. 2012

J. Clin. Invest.

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Cilia are highly specialized microtubule-based organelles that have pivotal roles in numerous biological processes, including transducing sensory signals. Defects in cilia biogenesis and transport cause pleiotropic human ciliopathies. Mutations in over 30 different genes can lead to cilia defects, and complex interactions exist among ciliopathy-associated proteins. Mutations of the centrosomal protein 290 kDa (CEP290) lead to distinct clinical manifestations, including Leber congenital amaurosis (LCA), a hereditary cause of blindness due to photoreceptor degeneration. Mice homozygous for a mutant Cep290 allele (Cep290 rd16 mice) exhibit LCA-like early-onset retinal degeneration that is caused by an in-frame deletion in the CEP290 protein. Here, we show that the domain deleted in the protein encoded by the Cep290 rd16 allele directly interacts with another ciliopathy protein, MKKS. MKKS mutations identified in patients with the ciliopathy BardetBiedl syndrome disrupted this interaction. In zebrafish embryos, combined subminimal knockdown of mkks and cep290 produced sensory defects in the eye and inner ear. Intriguingly, combinations of Cep290 rd16 and Mkks ko alleles in mice led to improved ciliogenesis and sensory functions compared with those of either mutant alone. We propose that altered association of CEP290 and MKKS affects the integrity of multiprotein complexes at the cilia transition zone and basal body. Amelioration of the sensory phenotypes caused by specific mutations in one protein by removal of an interacting domain/protein suggests a possible novel approach for treating human ciliopathies.

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“…CEP290 mutations have been described in up to 20% of cases of the devastating inherited blinding disease Leber congenital amaurosis (7,8) and in numerous cases of other more debilitating ciliopathies, such as Joubert syndrome (9-11), Senior-Løken syndrome (12), and Meckel-Gruber syndrome (13). How the many identified mutations in CEP290 contribute to these diverse pathologies remains unknown, and the protein's normal biological role has not been well characterized.…”

Section: Introductionmentioning

confidence: 99%

Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration

Drivas¹,

Holzbaur²,

Bennett³

2013

J. Clin. Invest.

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Mutations in the gene centrosomal protein 290 kDa (CEP290) cause an array of debilitating and phenotypically distinct human diseases, ranging from the devastating blinding disease Leber congenital amaurosis (LCA) to Senior-Løken syndrome, Joubert syndrome, and the lethal Meckel-Gruber syndrome. Despite its critical role in biology and disease, very little is known about CEP290's function. Here, we have identified 4 functional domains of the protein. We found that CEP290 directly binds to cellular membranes through an N-terminal domain that includes a highly conserved amphipathic helix motif and to microtubules through a domain located within its myosin-tail homology domain. Furthermore, CEP290 activity was regulated by 2 autoinhibitory domains within its N and C termini, both of which were found to play critical roles in regulating ciliogenesis. Disruption of the microtubule-binding domain in a mouse model of LCA was sufficient to induce significant deficits in cilium formation, which led to retinal degeneration. These data implicate CEP290 as an integral structural and regulatory component of the cilium and provide insight into the pathological mechanisms of LCA and related ciliopathies. Further, these data illustrate that disruption of particular CEP290 functional domains may lead to particular disease phenotypes and suggest innovative strategies for therapeutic intervention.

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Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior Loken syndrome

Abstract: Six novel and six known truncating mutations, one known missense mutation and one novel 3 bp pair in-frame deletion were identified in a total of seven families with JBTS, two families with SLSN and one family with isolated NPHP.

Cited by 95 publications

References 31 publications

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

Cilia localization is essential for in vivo functions of the Joubert syndrome protein Arl13b/Scorpion

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

Disruption of CEP290 microtubule/membrane-binding domains causes retinal degeneration

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