Ciliopathy

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Eukaryotic cilium diagram en.svg

A ciliopathy is a genetic disease of the cilia cells , their basic structure (for example the basal cells ) or a malfunction of the cilia.

introduction

Since cilia occur on almost all cell types in vertebrates , the elementary importance of these cell organelles is underlined. It facilitates the creation of a wide range of functionality. The main task is in the sensory area and a "motor for liquid flows". In the sensory area, the cilia play a role in mechanoreception , smell , light perception , chemo and thermoreceptors, and in monitoring osmotic pressure . The function “motor for fluid flows” exists intra- and extracellularly and has influences e.g. B. in fluid transport in the kidneys or the airways ( ciliated epithelium ). From this one can imagine the potency of the involvement of ciliopathies in many diseases. Malfunctions in the cilia are usually already noticeable in the embryonic development. In stem cell research on cells from mice and humans, the formation of a primary cilium was observed. This primary cilium is involved in elementary signaling pathways such as the Hedgehog (Hh) , Wnt , PDGF and FGF signaling pathways. The absence of cilia on the differentiating cells seems to be the exception. The presence of an intact and also differentiating ciliary apparatus seems to be essential for cell line development, since primary processes of the intercellular signal transmission pathways depend on it. Findings on this have so far been obtained from experiments with mice and the zebrafish popular with aquarists . Disturbances in the Hedgehog signal path lead to defects in the neural tube or maldevelopment of limbs (Shh sub-form). Impairments in the Wnt signal path also lead to neural tube defects and changes to the stereocilia in the inner ear . If there are other signal path disorders, changes in the GPCR lead to the development of Laurence-Moon-Biedl-Bardet syndrome . The formation of a polycystic kidney is related to u. a. with the cilia-dependent PDGF receptor-α . Disturbances of the mechanoreception were found with changes in the range of the calcium- and cAMP -controlled responses and led to right-left disturbances (e.g. situs inversus ) and polycystic kidneys.

Ciliopathies are predominantly associated with proteins, so far around 2,500 have been identified that are assigned to the cilia themselves or to the centrosomes . It is possible that other proteins, such as, for example, XPNPEP3 , which is located in mitochondria, presumably trigger proteolytic changes in the ciliary proteins, and thus disorders.

Diseases

Further knowledge of this group of diseases has only been gained since the mid-1990s, although many functions of these cell organelles in the various tissues are still unclear. One of the focal points of research was and is the question of why disorders of the cilia can trigger such severe clinical pictures. Since cilia are located on almost every cell and take on similar tasks there, the symptoms of diseases often overlap and matching mutations are often found in the same gene locations; the combination of the mutations results in different and / or additional syndrome patterns

In healthy organisms there are particularly "cilia-critical" areas:

Known ciliopathies

designation OMIM number Gen / e System / organs
Alström syndrome , 203800 ALMS1
Laurence-Moon-Biedl-Bardet 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 syndrome 249000 MKS1 , TMEM67 , TMEM216 , CEP290 , RPGRIP1L , CC2D2A Liver , heart , bones
Nephronophthisis 256100 NPHP1 , INVS , NPHP3 , NPHP4 , IQCB1 , CEP290 , GLIS2 , RPGRIP1L kidney
Oro-facio-digital syndrome type 1 311200 OFD1
Senior Loken Syndrome 266900 NPHP1 , NPHP4 , IQCB1 , CEP290 , SDCCAG8 eye
Cyst kidney 173900 PKD1 , PKD2 , PKHD1 kidney
Kartagener Syndrome / Primary Ciliary Dyskinesia 244400 DNAI1 , DNAH5 , TXNDC3 , DNAH11 , DNAI2 , KTU , RSPH4A , RSPH9 , LRRC50

Memo: All links to the loci are available on the English-language Wikipedia page

Other confirmed ciliopathies

Suspected ciliopathies

Above all, Badano formulated in his review article from 2006 a ciliopathy as a possible cause for these diseases or partially for the symptoms, which are considered to be quite global:

(Literature status up to 2008, no reliable confirmation from a PubMed search found by the end of 2011)

Individual evidence

  1. ↑ a b c Adams M, Smith UM, Logan CV, Johnson CA: (Free PDF article) Recent advances in the molecular pathology, cell biology and genetics of ciliopathies . In: Journal of Medical Genetics . 45, No. 5, 2008, pp. 257-267. PMID 18178628 . Retrieved October 10, 2012.
  2. ^ Lee JH, Gleeson JG: The role of primary cilia in neuronal function . In: Neurobiol. Dis. . 38, No. 2, May 2010, pp. 167-72. doi : 10.1016 / j.nbd.2009.12.022 . PMID 20097287 . PMC 2953617 (free full text).
  3. ↑ Gerdes JM, Davis EE, Katsanis N: The vertebrate primary cilium in Development, Homeostasis, and Disease . In: Cell . 137, 2009, pp. 32-45. doi : 10.1016 / j.cell.2009.03.023 . Retrieved February 5, 2012.
  4. ↑ Edwin C. and Katsanis N .: Cilia in vertebrate development and disease . In: Development . 139, 2012, pp. 443-448. doi : 10.1242 / dev.050054 .
  5. ↑ The Ciliary Proteome. Retrieved February 5, 2012 .
  6. ↑ Hurd TW, Hildebrandt F: Mechanisms of Nephronophthisis and Related Ciliopathies . In: Nephron Exp. Nephrol. . 118, No. 1, 2011, pp. E9 – e14. doi : 10.1159 / 000320888 . PMID 21071979 . PMC 2992643 (free full text).
  7. ↑ a b c d e f Davenport JR, Yoder BK: An incredible decade for the primary cilium: a look at a once-forgotten organelle Archived from the original on July 4, 2008. Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Am. J. Physiol. Renal Physiol. . 289, No. 6, 2005, pp. F1159-69. doi : 10.1152 / ajprenal.00118.2005 . PMID 16275743 . Retrieved June 30, 2008.  @1@ 2Template: Webachiv / IABot / ajprenal.physiology.org
  8. ↑ a b c The Ciliary Proteome , Ciliaproteome V3.0 - Home Page, Retrieved June 15, 2012.
  9. ↑ 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 Badano JL, Mitsuma N, Beales PL, Katsanis N: The ciliopathies: an emerging class of human genetic disorders . In: Annu Rev Genomics Hum Genet . 7, 2006, pp. 125-48. doi : 10.1146 / annurev.genom.7.080505.115610 . PMID 16722803 .
  10. ↑ a b c d e Ross A, Beales PL, Hill J: 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 , p. 177 (Accessed July 1, 2009).
  11. ↑ Tan PL, Barr T, Inglis PN, among others: Loss of Bardet – Biedl syndrome proteins causes defects in peripheral sensory innervation and function . In: Proc. Natl. Acad. Sci. USA . 104, No. 44, 2007, pp. 17524-9. doi : 10.1073 / pnas.0706618104 . PMID 17959775 . PMC 2077289 (free full text).
  12. ↑ Kyttälä M: Identification of the Meckel syndrome genes (MKS1) Exposes a Novel Ciliopathy Archived from the original on July 21, 2006. (pdf) In: National Public Health Institute, Helsinki (ed.) . May 2006. Retrieved July 6, 2008.  
  13. ↑ Dysplasia, cranio-ectodermal. In: Orphanet (Rare Disease Database).
  14. ^ Delgado-Escueta AV: Advances in Genetics of Juvenile Myoclonic Epilepsies . In: Epilepsy Curr . 7, No. 3, 2007, pp. 61-7. doi : 10.1111 / j.1535-7511.2007.00171.x . PMID 17520076 . PMC 1874323 (free full text).
  15. ↑ Khanna H et al .: A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies . In: Nature Genetics . 41, 2009, pp. 739-745. doi : 10.1038 / ng.366 .