The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4

Sayer, John A.; Otto, Edgar A.; O’Toole, John F.; Nürnberg, Gudrun; Kennedy, Michael A.; Becker, Christian; Hennies, Hans Christian; Helou, Juliana; Attanasio, Massimo; Fausett, Blake V.; Utsch, Boris; Khanna, Hemant; Liu, Yan; Drummond, Iain A.; Kawakami, Isao; Kusakabe, Takehiro; Tsuda, Motoyuki; Ma, Li; Lee, Hwankyu; Larson, Ronald G.; Allen, Susan J.; Wilkinson, C. D. W.; Nigg, Erich A.; Shou, Chengchao; Lillo, Concepción; Williams, David S.; Höppe, Bernd; Kemper, Markus J.; Neuhaus, Thomas J.; Parisi, Melissa A.; Glass, Ian A.; Petry, Marianne; Kispert, Andreas; Gloy, Joachim; Ganner, Athina; Walz, Gerd; Zhu, Xueliang; Goldman, Daniel; Nürnberg, Peter; Swaroop, Anand; Leroux, Michel R.; Hildebrandt, Friedhelm

doi:10.1038/ng1786

Cited by 524 publications

(556 citation statements)

References 27 publications

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“…These include Ableson-helper integration-1 (AHI1), Nephrocystin-1 (NPHP1), Centrosomal protein-290 (CEP290), Transmembrane protein 67 (TMEM67) and Retinitis pigmentosa GTPase regulator-interacting protein-like (RPGRIP1L). Each of the genes encodes a modular scaffolding protein without clear enzymatic domains, but sharing several protein-interaction domains of unknown function, suggesting that they may be part of a signaling complex [28][29][30][31][32][33][34][35][36] The Joubert syndrome connection with cilia Although the function of JSRD proteins remains largely unknown, recent evidence suggests roles in either mediating the assembly/stability of cilia or mediating cargo transport within cilia. When tested directly, at least three of the encoded proteins, NPHP1, CEP290 and RPGRIP1L have demonstrated localization to the basal body or cilium [32,[35][36][37], further suggesting a role at the cilium or basal body.…”

Section: Joubert Syndrome and Related Disordersmentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

170

141

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The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

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Section: Joubert Syndrome and Related Disordersmentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

170

141

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“…The gene product localizes to renal cilia and to the photoreceptor connecting cilium/transitional zone (9), and is required for early cilia assembly and ciliogenesis (13,14). Additionally, NPHP5 interacts with several proteins responsible for X-linked retinitis pigmentosa (RPGR) (15), LCA, SLSN or Joubert syndrome (CEP290) (10,16,17) and the BBSome subunits that have been implicated in Bardet Biedl Syndrome (18,19). The close interaction of these ciliary proteins, and the overlapping phenotypes observed when defective, suggests that they may function in the same or common pathways.…”

Section: Introductionmentioning

confidence: 99%

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

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“…However, it is apparent that depletion of the other zebrafish centrosomal proteins analysed thus far can also cause defects in the nervous system. Indeed, it has been demonstrated that depletion of the centrosomal protein CEP290 (nephrocystin-6) from zebrafish embryos results in developmental defects of the CNS such as smaller eyes and defects of the brain, 36 thereby highlighting the importance of centrosomal proteins in CNS development. In addition, depletion of CEP290 causes retinal degeneration and kidney abnormalities, because of its function in cilia.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, depletion of CEP290 causes retinal degeneration and kidney abnormalities, because of its function in cilia. 36,37 Depletion of other centrosomal proteins, Cep70 and Cep131, also results in embryos with a curved tail, shortened body axis and ectopic otoliths, because of shortened cilia. 38 Although not examined here, given the link between centrosomal proteins and ciliary function, and the localisation of NEDD1 to the base of cilia in mouse embryos, 5 it is feasible that zNEDD1 depletion also causes ciliary defects in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

An essential function for the centrosomal protein NEDD1 in zebrafish development

et al. 2010

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The centrosome is the primary microtubule organising centre of the cell. It is composed of many proteins, some of which make up the core of the centrosome, whereas others are used for specific functions. Although the cellular roles of many centrosomal proteins are well defined, much less is known about their functions and the role of the centrosome in development. In this study we investigated the function of NEDD1, a critical component of the centrosome essential for microtubule nucleation, in zebrafish (Danio rerio) development. The zebrafish homologue of NEDD1 (zNEDD1) was cloned and found to have a similar localisation and function to mammalian NEDD1. We show that zNEDD1 is essential for survival, as a high level of knockdown was embryonic lethal. Partial knockdown of zNEDD1 caused abnormalities including an increase in mitotic and apoptotic cells. Pronounced phenotypic defects were seen in the brain, with a lack of defined brain structures, incomplete neural tube formation and a disorganisation of neurons. In addition, we show that a reduction in zNEDD1 resulted in the loss of c-tubulin at the centrosome. Our data thus demonstrate that zNEDD1 is critical for the recruitment of c-tubulin to the centrosome, and is essential for the proper development of zebrafish. The centrosome is the major microtubule organising centre (MTOC) of cells and serves as a centralised location for controlling many cellular processes. The centrosomal protein neural precursor cell expressed developmentally downregulated gene 1 (NEDD1), 1 functions in the centrosomal and mitotic-spindle recruitment of the g-tubulin ring complex (g-TuRC). This complex is required for the nucleation of microtubules, correct formation of the mitotic spindle and hence progression of the cell cycle. 2,3 Because of this, depletion of NEDD1 from mammalian cells results in dispersion of the MTOC, impaired centrosomal and chromatin nucleation of microtubules, mitotic chaos and cell-cycle arrest. [2][3][4] Given the centrosomal localisation and function of NEDD1, and its dynamic expression during mouse embryogenesis, 5 it is expected that this protein has an important role during development. However, because of the early embryonic lethality of mouse knockouts of centrosomal proteins, including g-tubulin, it has not been possible to study the function of these proteins in later stages of development in this organism. 6,7 Zebrafish (Danio rerio) posses many benefits for developmental studies including the conservation of genes involved in cell growth and proliferation, 8 the rapid maturation of translucent embryos 9 and the ability to specifically deplete proteins of interest. 10 Although there has been much work analysing the cell cycle in zebrafish, 11 there has been limited analysis of the centrosome in this species. Therefore, this system was chosen as a model to study the role of NEDD1 during development. In addition, NEDD1 homologues have been described in Drosophila, Xenopus and Arabidopsis. [12][13][14] Despite the consistent centrosomal localisation o...

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The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4

Cited by 524 publications

References 27 publications

Cerebellar development and disease

Cerebellar development and disease

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

An essential function for the centrosomal protein NEDD1 in zebrafish development

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