The primary cilium

Fry, Andrew M.; Leaper, Michelle J; Bayliss, Richard

doi:10.4161/org.28910

Cited by 68 publications

(38 citation statements)

References 62 publications

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“…The primary cilium is a microtubule-based projection in non-dividing cells which serves as a sensory organelle and signaling hub that mediates numerous physiological roles [1, 2]. Originally viewed as a cellular appendage of unclear significance, defects of the cilium are now known to cause clinically recognizable developmental syndromes (ciliopathies), the phenotypic spectrum of which involves nearly every body organ [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Characterizing the morbid genome of ciliopathies

et al. 2016

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BackgroundCiliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete.ResultsWe applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population.ConclusionsOur study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1099-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Characterizing the morbid genome of ciliopathies

et al. 2016

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“…Cilia and flagella are organelles that play critical roles in cell and organismal biology, from driving motility to sensing the extracellular environment [1]. Cilia function requires a specific protein and lipid composition that is determined by gating mechanisms located at the base of the cilium [2–4].…”

Section: Introductionmentioning

confidence: 99%

Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone

et al. 2017

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SUMMARY The motility and signaling functions of the primary cilium require a unique protein and lipid composition that is determined by gating mechanisms localized at the base of the cilium. Several protein complexes localize to the gating zone and may regulate ciliary protein composition, however, the mechanisms of ciliary gating and the dynamics of the gating components are largely unknown. Here we used the BiFC (bimolecular fluorescence complementation) assay and report for the first time on the protein-protein interactions that occur between ciliary gating components and transiting cargoes during ciliary entry. We find that the nucleoporin Nup62 and the C-termini of the nephronophthisis (NPHP) proteins NPHP4 and NPHP5 interact with the axoneme-associated kinesin-2 motor KIF17 and thus spatially map to the inner region of the ciliary gating zone. Nup62 and NPHP4 exhibit rapid turnover at the transition zone and thus define dynamic components of the gate. We find that B9D1, AHI1 and the N-termini of NPHP4 and NPHP5 interact with the transmembrane protein SSTR3 and thus spatially map to the outer region of the ciliary gating zone. B9D1, AHI1 and NPHP5 exhibit little to no turnover at the transition zone and thus define components of a stable gating structure. These data provide the first comprehensive map of the molecular orientations of gating zone components along the inner-to-outer axis of the ciliary gating zone. These results advance our understanding of the functional roles of gating zone components in regulating ciliary protein composition.

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“…The primary cilium is a nearly ubiquitous organelle of non-proliferative vertebrate cells. This organelle functions as an antenna to sense extracellular stimuli via various ciliary membrane receptors and transmits these signals into the cell to initiate intracellular transduction cascades of different signaling pathways 1 2 3 4 . These include the Hedgehog, Wnt, planar cell polarity, FGF, Notch, mTor, PDGF and the Hippo signaling pathways 5 6 7 8 9 10 11 12 13 .…”

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confidence: 99%

DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects

Kessler

Wunderlich

Uebe

et al. 2015

Sci Rep

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Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.

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The primary cilium

Cited by 68 publications

References 62 publications

Characterizing the morbid genome of ciliopathies

Characterizing the morbid genome of ciliopathies

Protein Interaction Analysis Provides a Map of the Spatial and Temporal Organization of the Ciliary Gating Zone

DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects

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