ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3

Hoff, Sylvia; Halbritter, Jan; Epting, Daniel; Frank, Valeska; Nguyen, Thanh-Minh T.; Reeuwijk, Jeroen van; Boehlke, Christopher; Schell, Christoph; Yasunaga, Takayuki; Helmstädter, Martin; Mergen, Miriam; Filhol, Emilie; Boldt, Karsten; Horn, Nicola; Ueffing, Marius; Otto, Edgar A.; Eisenberger, Tobias; Elting, Mariet W.; Wijk, J. A. E. van; Böckenhauer, Detlef; Sebire, Neil J.; Rittig, Søren; Vyberg, Mogens; Ring, Troels; Pöhl, Martin; Pape, Lars; Neuhaus, Thomas J.; Soliman, Neveen A.; Koon, Sarah; Harris, Peter C.; Grahammer, Florian; Huber, Tobias B.; Kuehn, E. Wolfgang; Kramer-Zucker, Albrecht; Bolz, Hanno J.; Roepman, Ronald; Saunier, Sophie; Walz, Gerd; Hildebrandt, Friedhelm; Bergmann, Carsten; Lienkamp, Soeren S.

doi:10.1038/ng.2681

Cited by 180 publications

(233 citation statements)

References 31 publications

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“…[52][53][54][55][56][57][58][59][60][61] In this regard, NPHP2/inversin recruits and anchors NPHP3, NPHP9/Nek8, and the newly identified NPHP protein, Anks6, to a distinct region in the proximal cilium, the inversin compartment, and integrity of this module is essential for correct laterality establishment in organisms from zebrafish to humans. 15,[62][63][64][65][66][67][68] Inversin was first discovered for its role in L-R establishment 62 and, presumably, the inversin compartment impinges on the function of motile and/or sensory cilia at the embryonic node, 67,69 which is critical in breaking the embryonic bilateral symmetry through the generation of a net leftward flow of the embryonic fluid during gastrulation 8 (see also below). Consequently, NPHP patients occasionally present with laterality defects and associated complex CHD.…”

Section: Tetralogy Of Fallot Tofmentioning

confidence: 99%

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Cilia and coordination of signaling networks during heart development

et al. 2013

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Section: Tetralogy Of Fallot Tofmentioning

confidence: 99%

“…Consequently, NPHP patients occasionally present with laterality defects and associated complex CHD. 13,15,47,66,68,[70][71][72] At later stages of heart development, primary cilia may assist in coordinating signaling networks required for morphogenesis and maturation of the heart.…”

Section: Tetralogy Of Fallot Tofmentioning

confidence: 99%

Cilia and coordination of signaling networks during heart development

et al. 2013

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“…6 The first patient described here was analyzed with an average coverage of 100X, the second patient with an average coverage of about 46X (Supplementary Table 1). Potential sequence variants were confirmed by Sanger sequencing and shown to segregate.…”

Section: Next-generation Sequencing (Ngs)mentioning

confidence: 99%

Tectonic gene mutations in patients with Joubert syndrome

et al. 2014

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So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with MeckelGruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients.

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“…INVS co‐precipitates with N‐cadherin and catenins, including β‐catenin, as well as with calmodulin in polarized epithelial cells (Yasuhiko et al , 2001; Morgan et al , 2002b; Nurnberger et al , 2002; Saunier et al , 2005). INVS also coordinates with ANKS6 during the pathogenesis of NPHP2 (Hoff et al , 2013). Moreover, INVS interacts with Aurora A, thereby inhibiting phosphorylation and activation, which consequently interferes with HDAC6‐mediated cilia disassembly (Mergen et al , 2013).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation‐dependent Akt–Inversin interaction at the basal body of primary cilia

et al. 2016

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A primary cilium is a microtubule‐based sensory organelle that plays an important role in human development and disease. However, regulation of Akt in cilia and its role in ciliary development has not been demonstrated. Using yeast two‐hybrid screening, we demonstrate that Inversin (INVS) interacts with Akt. Mutation in the INVS gene causes nephronophthisis type II (NPHP2), an autosomal recessive chronic tubulointerstitial nephropathy. Co‐immunoprecipitation assays show that Akt interacts with INVS via the C‐terminus. In vitro kinase assays demonstrate that Akt phosphorylates INVS at amino acids 864–866 that are required not only for Akt interaction, but also for INVS dimerization. Co‐localization of INVS and phosphorylated form of Akt at the basal body is augmented by PDGF‐AA. Akt‐null MEF cells as well as siRNA‐mediated inhibition of Akt attenuated ciliary growth, which was reversed by Akt reintroduction. Mutant phosphodead‐ or NPHP2‐related truncated INVS, which lack Akt phosphorylation sites, suppress cell growth and exhibit distorted lumen formation and misalignment of spindle axis during cell division. Further studies will be required for elucidating functional interactions of Akt–INVS at the primary cilia for identifying the molecular mechanisms underlying NPHP2.

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ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3

Cited by 180 publications

References 31 publications

Cilia and coordination of signaling networks during heart development

Cilia and coordination of signaling networks during heart development

Tectonic gene mutations in patients with Joubert syndrome

Phosphorylation‐dependent Akt–Inversin interaction at the basal body of primary cilia

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