The nonmotile ciliopathies

Tobin, Jonathan L.; Beales, Philip L.

doi:10.1097/gim.0b013e3181a02882

Cited by 189 publications

(175 citation statements)

References 145 publications

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“…Despite many of these localizing to centrosomes and basal bodies, only a handful have known functions both in centrosomes and ciliogenesis, and these include CEP290 and the oral-facial-digital syndrome 1 (OFD1) protein. CEP290, OFD1 and a third ciliopathy protein, Bardet-Biedl syndrome (BBS4), also associate with centriolar satellites, electrondense granules concentrated around the PCM [116,117]. Through a detailed discussion of these factors, we will highlight key themes of ciliary research and aim to provide insight into the complex nature of ciliopathies.…”

Section: Ciliopathies (A) Primary Cilia Formation and Centriolar Satementioning

confidence: 99%

“…Second, CEP290 and OFD1 participate in multiple protein complexes during ciliogenesis, which could be differentially affected by mutations [122,123,126,143]. Last, patients often carry mutations in multiple ciliary genes [116]. As normal ciliary function is implicated in a growing number of fundamental signalling pathways, mutations causing suboptimal function will have wide-ranging effects in development and homoeostasis.…”

Section: Ciliopathies (A) Primary Cilia Formation and Centriolar Satementioning

confidence: 99%

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Small organelle, big responsibility: the role of centrosomes in development and disease

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

140

111

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The centrosome, a key microtubule organizing centre, is composed of centrioles, embedded in a protein-rich matrix. Centrosomes control the internal spatial organization of somatic cells, and as such contribute to cell division, cell polarity and migration. Upon exiting the cell cycle, most cell types in the human body convert their centrioles into basal bodies, which drive the assembly of primary cilia, involved in sensing and signal transduction at the cell surface. Centrosomal genes are targeted by mutations in numerous human developmental disorders, ranging from diseases exclusively affecting brain development, through global growth failure syndromes to diverse pathologies associated with ciliary malfunction. Despite our much-improved understanding of centrosome function in cellular processes, we know remarkably little of its role in the organismal context, especially in mammals. In this review, we examine how centrosome dysfunction impacts on complex physiological processes and speculate on the challenges we face when applying knowledge generated from in vitro and in vivo model systems to human development.

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Section: Ciliopathies (A) Primary Cilia Formation and Centriolar Satementioning

confidence: 99%

Section: Ciliopathies (A) Primary Cilia Formation and Centriolar Satementioning

confidence: 99%

Small organelle, big responsibility: the role of centrosomes in development and disease

Chavali

Pütz

Gergely

2014

Phil. Trans. R. Soc. B

140

111

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“…3A). Unlike mouse PCs that start expressing SHH when they integrate the PC cell layer (14,15), at gw 17, staining was detected in a subset of PCs that were still migrating (30) (Fig. 3A).…”

Section: Gcp Proliferation Is Similar In Cerebellar Vermis and Hemispmentioning

confidence: 99%

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

Aguilar

Meunier

Strehl

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Joubert syndrome (JS) and Meckel syndrome (MKS) are pleiotropic ciliopathies characterized by severe defects of the cerebellar vermis, ranging from hypoplasia to aplasia. Interestingly, ciliary conditional mutant mice have a hypoplastic cerebellum in which the proliferation of cerebellar granule cell progenitors (GCPs) in response to Sonic hedgehog (SHH) is severely reduced. This suggests that Shh signaling defects could contribute to the vermis hypoplasia observed in the human syndromes. As existing JS/MKS mutant mouse models suggest apparently contradictory hypotheses on JS/MKS etiology, we investigated Shh signaling directly on human fetal samples. First, in an examination of human cerebellar development, we linked the rates of GCP proliferation to the different levels and localizations of active Shh signaling and showed that the GCP possessed a primary cilium with CEP290 at its base. Second, we found that the proliferation of GCPs and their response to SHH were severely impaired in the cerebellum of subjects with JS/MKS and Jeune syndrome. Finally, we showed that the defect in GCP proliferation was similar in the cerebellar vermis and hemispheres in all patients with ciliopathy analyzed, suggesting that the specific cause of vermal hypo-/aplasia precedes this defect. Our results, obtained from the analysis of human samples, show that the hemispheres and the vermis are affected in JS/MKS and provide evidence of a defective cellular mechanism in these pathologic processes.cilia | granular neuron | hindbrain | developmental pathology J oubert syndrome (JS; Online Mendelian Inheritance in Man no. 213300) and Meckel syndrome (MKS; Online Mendelian Inheritance in Man no. 249000) are believed to represent the two extremes of the same multisystemic disorder. JS is characterized by a complex malformation of the cerebellum/brainstem, the most striking feature of which is hypoplasia or complete aplasia of the cerebellar vermis (1, 2). In MKS, which is lethal in utero, this defect is associated with occipital encephalocele or anencephaly, severely cystic kidneys, and abnormal liver and skeleton. To date, 16 genes responsible for JS (NPHP1, AHI1, ARL13B, INPP5E, KIF7, OFD1, TCTN1, and CEP41), MKS (MKS1, B9D1, and B9D2), or both (RPGRIP1L, CEP290, CC2D2A, TMEM216, TMEM67/MKS3, and TCTN2) have been identified (3-6). Although all JS/MKS genes encode a ciliary/basal body (BB) protein, which is compelling evidence that the primary cilium is involved in these pathologic conditions, the cellular mechanisms by which cilium dysfunction leads to severe brain malformations remain a mystery.Because the use of human subjects to study human pathologies is problematic, insight into diseases usually comes from the analysis of murine models. However, none of the currently available murine models of JS/MKS faithfully recapitulate the cerebellar phenotype seen in JS/MKS. Interestingly, in ciliary conditional mutant mice, the cerebellum is hypoplastic and Sonic hedgehog (Shh)-dependent proliferation of granule cell progenitors (GCPs) is sev...

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“…[1][2][3][4] These and other primary and secondary features of BBS are now known to reflect the phenotypic consequences of impaired ciliary function or ciliopathy, an expansive group of developmental disorders among which BBS features prominently. 5 Although much remains to be learned about the formation and function of these cellular appendages, a model has emerged in which postmitotic cells, no longer requiring centrioles to organize their mitotic spindles, migrate their centrioles close to the cell membrane where they form a basal body upon which a highly organized cytoskeletal structure starts budding until it forms a mature cilium that interacts with the surrounding environment via a repertoire of signaling cascades the integrity of which is dependent on intact antero-and retrograde intraflagellar transport. 6 Despite the clear demonstration of impaired ciliary function in all genetic models of BBS, the relationship between the various BBS genes (14 described to date) and cilia is not always straightforward and involves trafficking of vesicles for intraflagellar transport, chaperoning of proteins and yet unidentified roles.…”

Section: Introductionmentioning

confidence: 99%

In search of triallelism in Bardet–Biedl syndrome

et al. 2012

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Bardet-Biedl syndrome (BBS) is a model disease for ciliopathy in humans. The remarkable genetic heterogeneity that characterizes this disease is consistent with accumulating data on the interaction between the proteins encoded by the 14 BBS genes identified to date. Previous reports suggested that such interaction may also extend to instances of oligogenic inheritance in the form of triallelism which defies the long held view of BBS as an autosomal recessive disease. In order to investigate the magnitude of triallelism in BBS, we conducted a comprehensive analysis of all 14 BBS genes as well as the CCDC28B-modifier gene in a cohort of 29 BBS families, most of which are multiplex. Two in trans mutations in a BBS gene were identified in each of these families for a total of 20 mutations including 12 that are novel. In no instance did we observe two mutations in unaffected members of a given family, or observe the presence of a third allele that convincingly acted as a modifier of penetrance and supported the triallelic model of BBS. In addition to presenting a comprehensive genotype/phenotype overview of a large set of BBS mutations, including the occurrence of nonsyndromic retinitis pigmentosa in a family with a novel BBS9 mutation, our study argues in favor of straightforward autosomal recessive BBS in most cases.

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The nonmotile ciliopathies

Cited by 189 publications

References 145 publications

Small organelle, big responsibility: the role of centrosomes in development and disease

Small organelle, big responsibility: the role of centrosomes in development and disease

Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome

In search of triallelism in Bardet–Biedl syndrome

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