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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 ciliary function through proteolytic cleavage of ciliary proteins.
Significant advances in understanding the importance of cilia were made beginning in the mid-1990s. However, "the physiological role that this organelle plays in most tissues remains elusive." Additional studies of "how ciliary dysfunction can lead to such severe disease and developmental pathologies" is a subject of current research.
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". 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."
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. "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.
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.
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.
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. Primary cilia in the retina play a role in transferring nourishment to the non-vascularized rod and cone cells from the vascularized cells several micrometres behind the surface of the retina.
Signal transduction pathways involved include the Hedgehog signaling pathway and the Wnt signaling pathway.
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.
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."
"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".
|Bardet-Biedl syndrome,||209900||BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12|
|Joubert syndrome||213300||INPP5E, TMEM216, AHI1, NPHP1, CEP290, TMEM67, RPGRIP1L, ARL13B, CC2D2A, BRCC3||brain|
|Meckel-Gruber syndrome||249000||MKS1, TMEM67, TMEM216, CEP290, RPGRIP1L, CC2D2A||liver, heart, bone|
|nephronophthisis,||256100||NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L||kidney|
|orofaciodigital syndrome 1||311200||OFD1|
|Senior-Loken syndrome||266900||NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8||eye|
|polycystic kidney disease, (ADPKD and ARPKD)||173900||PKD1, PKD2, PKHD1||kidney|
|primary ciliary dyskinesia (Kartagener Syndrome)||244400||DNAI1, DNAH5, TXNDC3, DNAH11, DNAI2, KTU, RSPH4A, RSPH9, LRRC50|
|asphyxiating thoracic dysplasia (Jeune)[verification needed]||208500|
|Marden-Walker syndrome[verification needed]||248700|
|situs inversus/Isomerism[verification needed]||270100|
|?||?||IFT88||Novel form of ciliopathy and consequent anosmia, reported in 2012.|
Other identified ciliopathies
- early embryonic death (some cases)
- hydrocephalus (some cases)
- polycystic liver disease
- retinal degeneration (some forms)
Implied or suspected ciliopathies
- agenesis of the corpus callosum
- breathing abnomalities
- cerebellar vermis hypoplasia
- Dandy-Walker malformation
- Ellis-van Creveld syndrome
- eye movement abnormalities
- liver disease
- hypoplasia of the corpus callosum
- reproductive sterility
- Jeune asphyxiating thoracic dystrophy
- Juvenile myoclonic epilepsy (JME) 
- Marden-Walker syndrome
- "mental retardation/developmental delay" or "other cognitive defects"
- posterior encephalocele
- respiratory dysfunction
- "recurrent respiratory infections"
- renal cystic disease
- retinitis pigmentosa (some forms)
- sensorineural deafness
- situs inversus/Isomerism
- spina bifida
Clinical symptoms and ciliary roles
A wide variety of symptoms are potential clinical features of ciliopathy.
- Chemosensation abnormalities, typically via ciliated epithelial cellular dysfunction.
- Defective thermosensation or mechanosensation, often via ciliated epithelial cellular dysfunction.
- Cellular motility dysfunction
- Issues with displacement of extracellular fluid
- Paracrine signal transduction abnormalities
In organisms of normal health, cilia are critical for:
- Lee JH, Gleeson JG (May 2010). The role of primary cilia in neuronal function. Neurobiol. Dis. 38 (2): 167–72.
- Hurd TW, Hildebrandt F (2011). Mechanisms of Nephronophthisis and Related Ciliopathies. Nephron Exp. Nephrol. 118 (1): e9–e14.
- Gardiner, Mary Beth (September 2005). The Importance of Being Cilia. HHMI Bulletin 18 (2).
- Satir, Peter, Søren T. Christensen (2008-03-26). Structure and function of mammalian cilia. Histochemistry and Cell Biology 129 (6): 687–693. 1432-119X.
- Lancaster MA, Gleeson JG (June 2009). The primary cilium as a cellular signaling center: lessons from disease. Curr. Opin. Genet. Dev. 19 (3): 220–9.
- Badano JL, Mitsuma N, Beales PL, Katsanis N (2006). The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7: 125–48.
- D'Angelo A, Franco B (2009). The dynamic cilium in human diseases. Pathogenetics 2 (1): 3.
- Hayden EC (2008). Biological tools revamp disease classification. Nature 453 (7196): 709.
- Ross, Allison; PL Beales, J Hill (2008). The Clinical, Molecular, and Functional Genetics of Bardet-Biedl Syndrome, in Genetics of Obesity Syndromes, 177, Oxford University Press. URL accessed 2009-07-01.
- (2006-05)Identification of the Meckel Syndrome Gene (MKS1) Exposes a Novel Ciliopathy.
- Gunay-Aygun M (November 2009). Liver and Kidney Disease in Ciliopathies. Am J Med Genet C Semin Med Genet 151C (4): 296–306.
- Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model
- Delgado-Escueta AV (2007). Advances in Genetics of Juvenile Myoclonic Epilepsies. Epilepsy Curr 7 (3): 61–7.
- (2008). Ciliary proteome database, v3. Database introduction. Johns Hopkins University. URL accessed on 2009-01-07.
- Tan PL, Barr T, Inglis PN, et al. (2007). Loss of Bardet–Biedl syndrome proteins causes defects in peripheral sensory innervation and function. Proc. Natl. Acad. Sci. U.S.A. 104 (44): 17524–9.
- The Ciliary Proteome, Ciliaproteome V3.0 - Home Page, accessed 2010-06-11.
- The Ciliary Proteome Web Page at Johns Hopkins
- Katsanis Lab, The Center for Human Disease Modeling, Duke University
- Ciliopathy Alliance UK - alliance of medical researchers, doctors and patient organisations representing patients and families suffering from ciliopathy diseases
- Deafness Research UK - genetics and hearing loss links, including ciliopathy conditions
Template:Other genetic disorders by mechanism
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