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==The mechanism of ciliary function==
==The mechanism of ciliary function==
"In effect, the [motile cilium] is a [[Molecular machine|nanomachine]] composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Cilia "function as mechano- or chemosensors and as a cellular global positioning system to detect changes in the surrounding environment." For example, ciliary signaling plays a role in the initiation of cellular replacement after cell damage.<ref name="Satir2008"/> In addition to this sensory role mediating specific signaling cues, cilia play "a [[secretion|secretory]] role in which a soluble protein is released to have an effect downstream of the fluid flow" in epithelial cells, and can of course mediate fluid flow directly in the case of motile cilia.<ref name="Adams2008"/> Primary cilia in the [[retina]] play a role in transferring nourishment to the non-vascularized [[Rod cell|rod]] and [[Cone cell|cone]] cells from the [[Blood vessel|vascularized]] cells several microns behind the surface of the retina.
"In effect, the [motile cilium] is a [[Molecular machine|nanomachine]] composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Cilia "function as mechano- or chemosensors and as a cellular global positioning system to detect changes in the surrounding environment." For example, ciliary signaling plays a role in the initiation of cellular replacement after cell damage.<ref name="Satir2008"/>
In addition to this sensory role mediating specific signaling cues, cilia play "a [[secretion|secretory]] role in which a soluble protein is released to have an effect downstream of the fluid flow" in epithelial cells, and can of course mediate fluid flow directly in the case of motile cilia.<ref name="Adams2008"/> Primary cilia in the [[retina]] play a role in transferring nourishment to the non-vascularized [[Rod cell|rod]] and [[Cone cell|cone]] cells from the [[Blood vessel|vascularized]] cells several microns behind the surface of the retina.

Signal transduction pathways involved include the [[Hedgehog signaling pathway]] and the [[Wnt signaling pathway]].<ref name="pmid19439065">{{cite journal |author=D'Angelo A, Franco B |title=The dynamic cilium in human diseases |journal=Pathogenetics |volume=2 |issue=1 |pages=3 |year=2009 |pmid=19439065 |pmc=2694804 |doi=10.1186/1755-8417-2-3 |url=http://www.pathogeneticsjournal.com/content/2/1/3}}</ref>


==Similar genes can result in a range of different diseases==
==Similar genes can result in a range of different diseases==

Version vom 25. November 2010, 12:41 Uhr

Vorlage:Infobox disease A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies,[1] or of ciliary function.[2]

Although ciliopathies are usually considered to involve proteins that localize to the primary cilia or centrosomes, it is possible for ciliopathies to be associated with proteins such as XPNPEP3, which localizes to mitochondria but is believed to affect ciliiary function through proteolytic cleavage of ciliary proteins.[3]

History

Although non-motile or primary cilia were first described in 1898, "cell biologists largely ignored them." But "microscopists continued to document their presence in the cells of most vertebrate organisms." The "primary cilium was long considered--with few exceptions--to be a largely useless evolutionary vestige, a vestigial organelle. Recent research has revealed an initial understanding that cilia are essential to many of the body's organs"[4]. Many mammalian eukaryotic cells are ciliated with primary cilia. These primary cilia play important roles in chemosensation, mechanosensation, and thermosensation. Cilia may thus be "viewed as sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation."[5]

Recent advances in mammalian genetic research have facilitated the elucidation of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell.[6] "Numerous critical developmental signaling pathways" essential to cellular development have been discovered. These are principally but not exclusively found in the non-motile or primary cilia. A number of common observable characteristics of mammalian genetic disorders and diseases are caused by ciliary dysgenesis and dysfunction. Once identified, these characteristics thus describe a set of hallmarks of a ciliopathy[7].

Cilia have recently been implicated in a wide variety of human genetic diseases by "the discovery that numerous proteins involved in mammalian disease localize to the basal bodies and cilia." For example, in just a single area of human disease physiology, cystic renal disease, cilia-related genes and proteins have been identified to have causal effect in polycystic kidney disease, nephronophthisis, Senior-Loken syndrome type 5, orofaciodigital syndrome type 1 and Bardet-Biedl syndrome[8].

The mechanism of ciliary function

"In effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Cilia "function as mechano- or chemosensors and as a cellular global positioning system to detect changes in the surrounding environment." For example, ciliary signaling plays a role in the initiation of cellular replacement after cell damage.[5]

In addition to this sensory role mediating specific signaling cues, cilia play "a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow" in epithelial cells, and can of course mediate fluid flow directly in the case of motile cilia.[1] Primary cilia in the retina play a role in transferring nourishment to the non-vascularized rod and cone cells from the vascularized cells several microns behind the surface of the retina.

Signal transduction pathways involved include the Hedgehog signaling pathway and the Wnt signaling pathway.[9]

Similar genes can result in a range of different diseases

"Just as different genes can contribute to similar diseases, so the same genes and families of genes can play a part in a range of different diseases." For example, in just two of the diseases caused by malfunctioning cilia, Meckel-Gruber syndrome and Bardet-Biedl syndrome, patients who carry mutations in genes associated with both diseases "have unique symptoms that are not seen in either condition alone." The genes linked to the two different conditions "interact with each other during development." Systems biologists are endeavoring to define functional modules containing multiple genes and then look at disorders whose phenotypes fit into such modules.[10]

A particular phenotype can overlap "considerably with several conditions (ciliopathies) in which primary cilia are also implicated in pathogenicity. One emerging aspect is the wide spectrum of ciliopathy gene mutations found within different diseases."[11]

Ciliopathies

"The phenotypic parameters that define a ciliopathy may be used to both recognize the cellular basis of a number of genetic disorders and to facilitate the diagnosis and treatment of some diseases of unknown etiology"[7].

Condition OMIM Gene(s) Systems/organs
Alstrom syndrome[7],[1] Vorlage:OMIM2 ALMS1
Bardet-Biedl syndrome[7],[8][11] Vorlage:OMIM2 BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12
Joubert syndrome[7][11] Vorlage:OMIM2 INPP5E, TMEM216, AHI1, NPHP1, CEP290, TMEM67, RPGRIP1L, ARL13B, CC2D2A, BRCC3 brain
Meckel-Gruber syndrome[7][11] Vorlage:OMIM2 MKS1, TMEM67, TMEM216, CEP290, RPGRIP1L, CC2D2A liver, heart, bone
nephronophthisis[7],[8][11] Vorlage:OMIM2 NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L kidney
orofaciodigital syndrome 1[8][1] Vorlage:OMIM2 OFD1
Senior-Loken syndrome[8] Vorlage:OMIM2 NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8 eye
polycystic kidney disease[7],[8] (ADPKD and ARPKD)[12] Vorlage:OMIM2 PKD1, PKD2, PKHD1 kidney
primary ciliary dyskinesia[7] Vorlage:OMIM2 DNAI1
asphyxiating thoracic dysplasia (Jeune)[7]Vorlage:Verify source Vorlage:OMIM2
Marden-Walker syndrome[7]Vorlage:Verify source Vorlage:OMIM2
situs inversus/Isomerism[7]Vorlage:Verify source Vorlage:OMIM2

Other identified ciliopathies

Implied or suspected ciliopathies

Clinical symptoms and ciliac roles

A wide variety of symptoms are potential clinical features of ciliopathy.

In organisms of normal health, cilia are critical for:

References

Vorlage:Reflist

External links

Vorlage:Other genetic disorders by mechanism

  1. ↑ a b c d e f g M Adams, UM Smith, CV Logan, CA Johnson: Recent advances in the molecular pathology, cell biology and genetics of ciliopathies. In: Journal of Medical Genetics. 45. Jahrgang, Nr. 5. BMJ, 2008, S. 257–267, doi:10.1136/jmg, PMID 18178628 (bmj.com [abgerufen am 20. August 2009]).
  2. ↑ Lee JH, Gleeson JG: The role of primary cilia in neuronal function. In: Neurobiol. Dis. 38. Jahrgang, Nr. 2, Mai 2010, S. 167–72, doi:10.1016/j.nbd.2009.12.022, PMID 20097287, PMC 2953617 (freier Volltext) – (elsevier.com).
  3. ↑ Hurd TW, Hildebrandt F: Mechanisms of nephronophthisis and related ciliopathies. In: Nephron Exp. Nephrol. 118. Jahrgang, Nr. 1, 2011, S. e9–e14, doi:10.1159/000320888, PMID 21071979 (karger.com).
  4. ↑ Mary Beth Gardiner: The Importance of Being Cilia. In: HHMI Bulletin. 18. Jahrgang, Nr. 2. Howard Hughes Medical Institute, September 2005 (hhmi.org [abgerufen am 26. Juli 2008]).
  5. ↑ a b Peter Satir, Søren T. Christensen: Structure and function of mammalian cilia. In: Histochemistry and Cell Biology. 129. Jahrgang, Nr. 6. Springer Berlin / Heidelberg, 26. März 2008, 1432-119X, S. 687–693, doi:10.1007/s00418-008-0416-9, PMID 18365235, PMC 2386530 (freier Volltext) – (springerlink.com [abgerufen am 12. September 2009]).
  6. ↑ Lancaster MA, Gleeson JG: The primary cilium as a cellular signaling center: lessons from disease. In: Curr. Opin. Genet. Dev. 19. Jahrgang, Nr. 3, Juni 2009, S. 220–9, doi:10.1016/j.gde.2009.04.008, PMID 19477114, PMC 2953615 (freier Volltext) – (elsevier.com).
  7. ↑ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq Badano JL, Mitsuma N, Beales PL, Katsanis N: The ciliopathies: an emerging class of human genetic disorders. In: Annu Rev Genomics Hum Genet. 7. Jahrgang, 2006, S. 125–48, doi:10.1146/annurev.genom.7.080505.115610, PMID 16722803 (annualreviews.org).
  8. ↑ a b c d e f Davenport JR, Yoder BK: An incredible decade for the primary cilium: a look at a once-forgotten organelle. In: Am. J. Physiol. Renal Physiol. 289. Jahrgang, Nr. 6, 2005, S. F1159–69, doi:10.1152/ajprenal.00118.2005, PMID 16275743 (physiology.org).
  9. ↑ D'Angelo A, Franco B: The dynamic cilium in human diseases. In: Pathogenetics. 2. Jahrgang, Nr. 1, 2009, S. 3, doi:10.1186/1755-8417-2-3, PMID 19439065, PMC 2694804 (freier Volltext) – (pathogeneticsjournal.com).
  10. ↑ Hayden EC: Biological tools revamp disease classification. In: Nature. 453. Jahrgang, Nr. 7196, 2008, S. 709, doi:10.1038/453709a, PMID 18528360 (nature.com [SCHOLAR SEARCH]).
  11. ↑ a b c d e f Allison Ross, PL Beales, J Hill: The Clinical, Molecular, and Functional Genetics of Bardet-Biedl Syndrome, in Genetics of Obesity Syndromes. Oxford University Press, 2008, ISBN 978-0-19-530016-1, S. 177 (google.com [abgerufen am 1. Juli 2009]).
  12. ↑ Gunay-Aygun M: Liver and kidney disease in ciliopathies. In: Am J Med Genet C Semin Med Genet. 151C. Jahrgang, Nr. 4, November 2009, S. 296–306, doi:10.1002/ajmg.c.30225, PMID 19876928, PMC 2919058 (freier Volltext) – (doi.org).
  13. ↑ Delgado-Escueta AV: Advances in genetics of juvenile myoclonic epilepsies. In: Epilepsy Curr. 7. Jahrgang, Nr. 3, 2007, S. 61–7, doi:10.1111/j.1535-7511.2007.00171.x, PMID 17520076, PMC 1874323 (freier Volltext).
  14. ↑ A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies, Nature Genetics 41, pp. 739-745, 2009-05, accessed 2010-11-24.
  15. ↑ a b c d Ciliary proteome database, v3. In: Database introduction. Johns Hopkins University, 2008, abgerufen am 7. Januar 2009.
  16. ↑ Tan PL, Barr T, Inglis PN, et al.: Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function. In: Proc. Natl. Acad. Sci. U.S.A. 104. Jahrgang, Nr. 44, 2007, S. 17524–9, doi:10.1073/pnas.0706618104, PMID 17959775, PMC 2077289 (freier Volltext) – (pnas.org).
  17. ↑ a b c The Ciliary Proteome, Ciliaproteome V3.0 - Home Page, accessed 2010-06-11.
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