Medicine:Ciliopathy

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Short description: Genetic disease resulting in abnormal formation or function of cilia
Ciliopathy
Eukaryotic cilium diagram en.svg
Eukaryotic cilium

A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies,[1] or ciliary function.[2] Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem.[3] The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.

Although ciliopathies are usually considered to involve proteins that localize to motile and/or immotile (primary) cilia or centrosomes, it is possible for ciliopathies to be associated with unexpected proteins such as XPNPEP3, which localizes to mitochondria but is believed to affect ciliary function through proteolytic cleavage of ciliary proteins.[4]

Significant advances in understanding the importance of cilia were made 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 still a subject of current research.[5]

Signs and symptoms

A wide variety of symptoms are potential clinical features of ciliopathy. The signs most exclusive to a ciliopathy, in descending order of exclusivity, are:[6]:138

A case with polycystic ovary syndrome, multiple subcutaneous cysts, renal function impairment, Caroli disease and liver cirrhosis due to ciliopathy has been described.[7]

Phenotypes sometimes associated with ciliopathies can include:[6]

Pathophysiology

"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.[9]

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 pigment epithelial vascularized cells several micrometres behind the surface of the retina.

Signal transduction pathways involved include the Hedgehog signaling pathway and the Wnt signaling pathway.[10]

Dysfunctional cilia can lead to:

In organisms of normal health, cilia are critical for:[13]

Genetics

"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.[14]

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."[8]

List of 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" cause.[6]

Known ciliopathies

Condition OMIM Gene(s) Systems/organs affected
Alström syndrome[6][1] Online Mendelian Inheritance in Man (OMIM) 203800 ALMS1
Asphyxiating thoracic dysplasia (Jeune syndrome)[6][15] Online Mendelian Inheritance in Man (OMIM) 208500
Bardet–Biedl syndrome[6][5][8] Online Mendelian Inheritance in Man (OMIM) 209900 BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12
Ellis–van Creveld syndrome[15] Online Mendelian Inheritance in Man (OMIM) 225500 EVC, EVC2
Joubert syndrome[6][8] Online Mendelian Inheritance in Man (OMIM) 213300 INPP5E, TMEM216, AHI1, NPHP1, CEP290, TMEM67, RPGRIP1L, ARL13B, CC2D2A, BRCC3 Brain
Leber congenital amaurosis[15] Online Mendelian Inheritance in Man (OMIM) 204000 GUCY2D, RPE65
McKusick–Kaufman syndrome[15] Online Mendelian Inheritance in Man (OMIM) 236700 MKKS
Meckel–Gruber syndrome[6][8][16] Online Mendelian Inheritance in Man (OMIM) 249000 MKS1, TMEM67, TMEM216, CEP290, RPGRIP1L, CC2D2A Liver, heart, bone
Nephronophthisis[6][5][8] Online Mendelian Inheritance in Man (OMIM) 256100 NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L Kidney
Orofaciodigital syndrome 1[1][5] Online Mendelian Inheritance in Man (OMIM) 311200 OFD1
Polycystic kidney disease[6][5] (ADPKD and ARPKD)[17] Online Mendelian Inheritance in Man (OMIM) 173900 PKD1, PKD2, PKHD1 Kidney
Primary ciliary dyskinesia (Kartagener syndrome)[6] Online Mendelian Inheritance in Man (OMIM) 244400 DNAI1, DNAH5, TXNDC3, DNAH11, DNAI2, KTU, RSPH4A, RSPH9, LRRC50
Senior–Løken syndrome[5] Online Mendelian Inheritance in Man (OMIM) 266900 NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8 Eye
Sensenbrenner syndrome (cranioectodermal dysplasia)[15] Online Mendelian Inheritance in Man (OMIM) 218330 IFT122
Short rib–polydactyly syndrome[15] Online Mendelian Inheritance in Man (OMIM) 613091 DYNC2H1
? ? IFT88 Novel form of congenital anosmia, reported in 2012[18]

Likely ciliopathies

Condition OMIM Gene(s) Systems/organs affected
Acrocallosal syndrome[15] Online Mendelian Inheritance in Man (OMIM) 200990 KIF7, GLI3
Acromelic frontonasal dysostosis[15] Online Mendelian Inheritance in Man (OMIM) 603671 ZSWIM6
Arima syndrome[15] Online Mendelian Inheritance in Man (OMIM) 243910
Biemond syndrome[15] Online Mendelian Inheritance in Man (OMIM) 113400
COACH syndrome[15] Online Mendelian Inheritance in Man (OMIM) 216360 TMEM67, CC2D2A, RPGRIP1L
Conorenal syndrome[19][15] Online Mendelian Inheritance in Man (OMIM) 266920
Greig cephalopolysyndactyly syndrome[15] Online Mendelian Inheritance in Man (OMIM) 175700 GLI3
Hydrolethalus syndrome[15] Online Mendelian Inheritance in Man (OMIM) 236680 HYLS1
Johanson–Blizzard syndrome[15] Online Mendelian Inheritance in Man (OMIM) 243800 UBR1
Mohr syndrome (oral-facial-digital syndrome type 2)[15] Online Mendelian Inheritance in Man (OMIM) 252100
Neu–Laxova syndrome[15] Online Mendelian Inheritance in Man (OMIM) 256520 PHGDH, PSAT1, PSPH
Opitz G/BBB syndrome[15] Online Mendelian Inheritance in Man (OMIM) 300000 MID1
Pallister–Hall syndrome[15] Online Mendelian Inheritance in Man (OMIM) 146510 GLI3
Papillorenal syndrome[15] Online Mendelian Inheritance in Man (OMIM) 120330 PAX2
Renal–hepatic–pancreatic dysplasia[15] Online Mendelian Inheritance in Man (OMIM) 208540 NPHP3
Varadi–Papp syndrome (oral-facial-digital syndrome type 6)[15] Online Mendelian Inheritance in Man (OMIM) 277170

Possible ciliopathies

Condition OMIM Gene(s) Systems/organs affected
Acrofacial dysostosis[15]
Acrofrontofacionasal dysostosis 2[15] Online Mendelian Inheritance in Man (OMIM) 239710
Adams–Oliver syndrome[15] Online Mendelian Inheritance in Man (OMIM) 100300 ARHGAP31, DOCK6, RBPJ, EOGT, NOTCH1, DLL4
Asplenia with cardiovascular anomalies (Ivemark syndrome)[15] Online Mendelian Inheritance in Man (OMIM) 208530
Autosomal recessive spastic paraplegia[15]
Barakat syndrome (HDR syndrome)[15] Online Mendelian Inheritance in Man (OMIM) 146255 GATA3
Basal cell nevus syndrome[15] Online Mendelian Inheritance in Man (OMIM) 109400 PTCH1, PTCH2, SUFU
Branchio‐oculo‐facial syndrome[15] Online Mendelian Inheritance in Man (OMIM) 113620 TFAP2A
C syndrome (Opitz trigonocephaly)[15] Online Mendelian Inheritance in Man (OMIM) 211750 CD96
Carpenter syndrome[15] Online Mendelian Inheritance in Man (OMIM) 201000 RAB23
Cephaloskeletal dysplasia (microcephalic osteodysplastic primordial dwarfism type 1)[15] Online Mendelian Inheritance in Man (OMIM) 210710 RNU4ATAC
Cerebrofaciothoracic dysplasia[15] Online Mendelian Inheritance in Man (OMIM) 213980 TMCO1
Cerebrofrontofacial syndrome (Baraitser–Winter syndrome)[15] Online Mendelian Inheritance in Man (OMIM) 243310 ACTB
Cerebrooculonasal syndrome[15] Online Mendelian Inheritance in Man (OMIM) 605627
Autosomal recessive spastic ataxia of Charlevoix-Saguenay[15] Online Mendelian Inheritance in Man (OMIM) 270550 SACS
Chondrodysplasia punctata 2[15] Online Mendelian Inheritance in Man (OMIM) 302960 EBP
Choroideremia[15] Online Mendelian Inheritance in Man (OMIM) 303100 CHM
Chudley–McCullough syndrome[15] Online Mendelian Inheritance in Man (OMIM) 604213 GPSM2
C‐like syndrome[15] Online Mendelian Inheritance in Man (OMIM) 605039 ASXL1
Coffin–Siris syndrome[15] Online Mendelian Inheritance in Man (OMIM) 135900 ARID1B, SOX11, ARID2
Cohen syndrome[15] Online Mendelian Inheritance in Man (OMIM) 216550 VPS13B
Craniofrontonasal dysplasia[15] Online Mendelian Inheritance in Man (OMIM) 304110 EFNB1
Dysgnathia complex[15] Online Mendelian Inheritance in Man (OMIM) 202650
Ectrodactyly–ectodermal dysplasia–cleft syndrome type 1[15] Online Mendelian Inheritance in Man (OMIM) 129900
Endocrine–cerebroosteodysplasia syndrome[15] Online Mendelian Inheritance in Man (OMIM) 612651 ICK
Focal dermal hypoplasia[15] Online Mendelian Inheritance in Man (OMIM) 305600 PORCN
Frontonasal dysplasia[15] Online Mendelian Inheritance in Man (OMIM) 136760 ALX3, ALX4, ALX1
Fryns microphthalmia syndrome[15] Online Mendelian Inheritance in Man (OMIM) 600776
Fryns syndrome[15] Online Mendelian Inheritance in Man (OMIM) 229850
Genitopatellar syndrome[15] Online Mendelian Inheritance in Man (OMIM) 606170 KAT6B
Hemifacial microsomia[15] Online Mendelian Inheritance in Man (OMIM) 164210
Hypothalamic hamartomas[15] Online Mendelian Inheritance in Man (OMIM) 241800
Johnson neuroectodermal syndrome[15] Online Mendelian Inheritance in Man (OMIM) 147770
Juvenile myoclonic epilepsy[20] Online Mendelian Inheritance in Man (OMIM) 254770
Kabuki syndrome[15] Online Mendelian Inheritance in Man (OMIM) 147920 KMT2D, KDM6A
Kallmann syndrome[15] Online Mendelian Inheritance in Man (OMIM) 308700 ANOS1
Lenz–Majewski hyperostotic dwarfism[15] Online Mendelian Inheritance in Man (OMIM) 151050 PTDSS1
Lissencephaly 3[15] Online Mendelian Inheritance in Man (OMIM) 611603 TUBA1A
Marden–Walker syndrome[6][15] Online Mendelian Inheritance in Man (OMIM) 248700 PIEZO2
MASA syndrome[15] Online Mendelian Inheritance in Man (OMIM) 303350 L1CAM
Microhydranencephaly[15] Online Mendelian Inheritance in Man (OMIM) 605013 NDE1
Mowat–Wilson syndrome[15] Online Mendelian Inheritance in Man (OMIM) 235730 ZEB2
NDH syndrome[15] Online Mendelian Inheritance in Man (OMIM) 610199 GLIS3
Oculoauriculofrontonasal syndrome[15] Online Mendelian Inheritance in Man (OMIM) 601452
Oculocerebrocutaneous syndrome[15] Online Mendelian Inheritance in Man (OMIM) 164180
Oculodentodigital dysplasia[15] Online Mendelian Inheritance in Man (OMIM) 164200 GJA1
Optiz–Kaveggia syndrome[15] Online Mendelian Inheritance in Man (OMIM) 305450 MED12
Otopalatodigital syndrome 2[15] Online Mendelian Inheritance in Man (OMIM) 304120 FLNA
Periventricular heterotopia X‐linked[15] Online Mendelian Inheritance in Man (OMIM) 300049 FLNA
Perlman syndrome[15] Online Mendelian Inheritance in Man (OMIM) 267000 DIS3L2
Pitt–Hopkins syndrome[15] Online Mendelian Inheritance in Man (OMIM) 610954 TCF4
Polycystic liver disease[6] Online Mendelian Inheritance in Man (OMIM) 174050
Proteus syndrome[15] Online Mendelian Inheritance in Man (OMIM) 176920 AKT1
Pseudotrisomy 13[15] Online Mendelian Inheritance in Man (OMIM) 264480
Retinal cone dystrophy 1[15] Online Mendelian Inheritance in Man (OMIM) 180020
Some forms of retinitis pigmentosa[6][21][15] Online Mendelian Inheritance in Man (OMIM) 268000
Robinow syndrome[15] Online Mendelian Inheritance in Man (OMIM) 268310 ROR2
Rubinstein–Taybi syndrome[15] Online Mendelian Inheritance in Man (OMIM) 180849 CREBBP
Sakoda complex[15] Online Mendelian Inheritance in Man (OMIM) 610871
Schinzel–Giedion syndrome[15] Online Mendelian Inheritance in Man (OMIM) 269150 SETBP1
Split-hand/foot malformation 3[15] Online Mendelian Inheritance in Man (OMIM) 246560
Spondyloepiphyseal dysplasia congenita[15] Online Mendelian Inheritance in Man (OMIM) 183900 COL2A1
Thanatophoric dysplasia[15] Online Mendelian Inheritance in Man (OMIM) 187600 FGFR3
Townes–Brocks syndrome[15] Online Mendelian Inheritance in Man (OMIM) 107480 SALL1, DACT1
Tuberous sclerosis[15] Online Mendelian Inheritance in Man (OMIM) 191100 TSC1, TSC2
VATER association[15] Online Mendelian Inheritance in Man (OMIM) 192350
Ven den Ende–Gupta syndrome[15] Online Mendelian Inheritance in Man (OMIM) 600920 SCARF2
Visceral heterotaxy[15] Online Mendelian Inheritance in Man (OMIM) 606325
Walker–Warburg syndrome[15] Online Mendelian Inheritance in Man (OMIM) 236670
Warburg Micro syndrome[15] Online Mendelian Inheritance in Man (OMIM) 615663 RAB3GAP1
X‐linked congenital hydrocephalus[15] Online Mendelian Inheritance in Man (OMIM) 307000 L1CAM
X‐linked lissencephaly[15] Online Mendelian Inheritance in Man (OMIM) 300067 DCX
Young–Simpson syndrome[15] Online Mendelian Inheritance in Man (OMIM) 603736 KAT6B

History

Although non-motile or primary cilia were first described in 1898, they were largely ignored by biologists. However, 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 that cilia are essential to many of the body's organs.[22] 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."[9]

Recent advances in mammalian genetic research have made possible the understanding of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell.[23] A number of 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.[6]

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–Løken syndrome type 5, orofaciodigital syndrome type 1 and Bardet–Biedl syndrome.[5]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Adams, M.; Smith, U. M.; Logan, C. V.; Johnson, C. A. (2008). "Recent advances in the molecular pathology, cell biology and genetics of ciliopathies". Journal of Medical Genetics 45 (5): 257–267. doi:10.1136/jmg.2007.054999. PMID 18178628. 
  2. "The role of primary cilia in neuronal function". Neurobiol. Dis. 38 (2): 167–72. May 2010. doi:10.1016/j.nbd.2009.12.022. PMID 20097287. 
  3. Powles-Glover, N (September 2014). "Cilia and ciliopathies: classic examples linking phenotype and genotype-an overview.". Reproductive Toxicology (Elmsford, N.Y.) 48: 98–105. doi:10.1016/j.reprotox.2014.05.005. PMID 24859270. 
  4. "Mechanisms of Nephronophthisis and Related Ciliopathies". Nephron Exp. Nephrol. 118 (1): e9–e14. 2011. doi:10.1159/000320888. PMID 21071979. 
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Davenport, J. R. (2005). "An incredible decade for the primary cilium: A look at a once-forgotten organelle". AJP: Renal Physiology 289 (6): F1159–F1169. doi:10.1152/ajprenal.00118.2005. PMID 16275743. 
  6. 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 "The ciliopathies: an emerging class of human genetic disorders". Annu Rev Genom Hum Genet 7: 125–48. 2006. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. 
  7. Tan K, Liu P, Pang L, Yang W, Hou F (2018) A human ciliopathy with polycystic ovarian syndrome and multiple subcutaneous cysts: A rare case report. Medicine (Baltimore) 97(50)
  8. 8.0 8.1 8.2 8.3 8.4 8.5 Ross, Allison; PL Beales; J Hill (2008). The Clinical, Molecular, and Functional Genetics of Bardet-Biedl Syndrome, in Genetics of Obesity Syndromes. Oxford University Press. pp. 177. ISBN 978-0-19-530016-1. https://books.google.com/books?id=SOvEYxO2V4AC. Retrieved 2009-07-01. 
  9. 9.0 9.1 Satir, Peter; Søren T. Christensen (2008-03-26). "Structure and function of mammalian cilia". Histochemistry and Cell Biology (Springer Berlin / Heidelberg) 129 (6): 687–693. doi:10.1007/s00418-008-0416-9. 1432-119X. PMID 18365235. 
  10. "The dynamic cilium in human diseases". Pathogenetics 2 (1): 3. 2009. doi:10.1186/1755-8417-2-3. PMID 19439065. 
  11. 11.0 11.1 11.2 11.3 "Ciliary proteome database, v3". Database introduction. Johns Hopkins University. 2008. http://v3.ciliaproteome.org/cgi-bin/index.php. Retrieved 2009-01-07. 
  12. "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. 2007. doi:10.1073/pnas.0706618104. PMID 17959775. 
  13. of organs The Ciliary Proteome , Ciliaproteome V3.0 - Home Page, accessed 2010-06-11.
  14. Hayden EC (2008). "Biological tools revamp disease classification". Nature 453 (7196): 709. doi:10.1038/453709a. PMID 18528360. 
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  16. Kyttälä, Mira (May 2006). Identification of the Meckel Syndrome Gene (MKS1) Exposes a Novel Ciliopathy. National Public Health Institute, Helsinki. http://www.ktl.fi/attachments/suomi/julkaisut/julkaisusarja_a/2006/2006a05.pdf. Retrieved 2008-07-06. 
  17. Gunay-Aygun M (November 2009). "Liver and Kidney Disease in Ciliopathies". Am J Med Genet C Semin Med Genet 151C (4): 296–306. doi:10.1002/ajmg.c.30225. PMID 19876928. 
  18. Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model
  19. "From cilia to cyst". Nat. Genet. 34 (4): 355–6. August 2003. doi:10.1038/ng0803-355. PMID 12923538. 
  20. Delgado-Escueta AV (2007). "Advances in Genetics of Juvenile Myoclonic Epilepsies". Epilepsy Curr 7 (3): 61–7. doi:10.1111/j.1535-7511.2007.00171.x. PMID 17520076. 
  21. Khanna, H.; Davis, E. E.; Murga-Zamalloa, C. A. et al. (2009). "A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies". Nature Genetics 41 (6): 739–745. doi:10.1038/ng.366. PMID 19430481. 
  22. Gardiner, Mary Beth (September 2005). "The Importance of Being Cilia". HHMI Bulletin (Howard Hughes Medical Institute) 18 (2). http://www.hhmi.org/bulletin/sept2005/features/cilia.html. Retrieved 2008-07-26. 
  23. "The primary cilium as a cellular signaling center: lessons from disease". Curr. Opin. Genet. Dev. 19 (3): 220–9. June 2009. doi:10.1016/j.gde.2009.04.008. PMID 19477114. 

External links

Classification
External resources