ciliopathy ciliopathy a ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. 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. 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. ciliopathyeukaryotic ciliumspecialtymedical genetics 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. 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. 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:: 138 dandy–walker malformation (cerebellar vermis hypoplasia, usually with hydrocephalus) agenesis of the corpus callosum situs inversus posterior encephalocele polycystic kidneys postaxial polydactyly liver disease retinitis pigmentosa intellectual disability a case with polycystic ovary syndrome, multiple subcutaneous cysts, renal function impairment, caroli disease and liver cirrhosis due to ciliopathy has been described. phenotypes sometimes associated with ciliopathies can include: anencephaly breathing abnormalities cerebellar vermis hypoplasia diabetes exencephaly eye movement abnormalities hydrocephalus hypoplasia of the corpus callosum hypotonia infertility cognitive impairment/defects obesity other polydactyly respiratory dysfunction renal cystic disease retinal degeneration sensorineural deafness spina bifida 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. 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 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. dysfunctional cilia can lead to: 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: development homeostasis reproduction 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. 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." 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. known ciliopathies condition omim gene(s) systems/organs affected alström syndrome 203800 alms1 asphyxiating thoracic dysplasia (jeune syndrome) 208500 bardet–biedl syndrome 209900 bbs1, bbs2, arl6, bbs4, bbs5, mkks, bbs7, ttc8, bbs9, bbs10, trim32, bbs12 ellis–van creveld syndrome 225500 evc, evc2 joubert syndrome 213300 inpp5e, tmem216, ahi1, nphp1, cep290, tmem67, rpgrip1l, arl13b, cc2d2a, brcc3 brain leber congenital amaurosis 204000 gucy2d, rpe65 mckusick–kaufman syndrome 236700 mkks 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 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 senior–løken syndrome 266900 nphp1, nphp4, iqcb1, cep290, sdccag8 eye sensenbrenner syndrome (cranioectodermal dysplasia) 218330 ift122 short rib–polydactyly syndrome 613091 dync2h1 ? ? ift88 novel form of congenital anosmia, reported in 2012 likely ciliopathies condition omim gene(s) systems/organs affected acrocallosal syndrome 200990 kif7, gli3 acromelic frontonasal dysostosis 603671 zswim6 arima syndrome 243910 biemond syndrome 113400 coach syndrome 216360 tmem67, cc2d2a, rpgrip1l conorenal syndrome 266920 greig cephalopolysyndactyly syndrome 175700 gli3 hydrolethalus syndrome 236680 hyls1 johanson–blizzard syndrome 243800 ubr1 mohr syndrome (oral-facial-digital syndrome type 2) 252100 neu–laxova syndrome 256520 phgdh, psat1, psph opitz g/bbb syndrome 300000 mid1 pallister–hall syndrome 146510 gli3 papillorenal syndrome 120330 pax2 renal–hepatic–pancreatic dysplasia 208540 nphp3 varadi–papp syndrome (oral-facial-digital syndrome type 6) 277170 possible ciliopathies condition omim gene(s) systems/organs affected acrofacial dysostosis acrofrontofacionasal dysostosis 2 239710 adams–oliver syndrome 100300 arhgap31, dock6, rbpj, eogt, notch1, dll4 asplenia with cardiovascular anomalies (ivemark syndrome) 208530 autosomal recessive spastic paraplegia barakat syndrome (hdr syndrome) 146255 gata3 basal cell nevus syndrome 109400 ptch1, ptch2, sufu branchio‐oculo‐facial syndrome 113620 tfap2a c syndrome (opitz trigonocephaly) 211750 cd96 carpenter syndrome 201000 rab23 cephaloskeletal dysplasia (microcephalic osteodysplastic primordial dwarfism type 1) 210710 rnu4atac cerebrofaciothoracic dysplasia 213980 tmco1 cerebrofrontofacial syndrome (baraitser–winter syndrome) 243310 actb cerebrooculonasal syndrome 605627 autosomal recessive spastic ataxia of charlevoix-saguenay 270550 sacs chondrodysplasia punctata 2 302960 ebp choroideremia 303100 chm chudley–mccullough syndrome 604213 gpsm2 c‐like syndrome 605039 asxl1 coffin–siris syndrome 135900 arid1b, sox11, arid2 cohen syndrome 216550 vps13b craniofrontonasal dysplasia 304110 efnb1 dysgnathia complex 202650 ectrodactyly–ectodermal dysplasia–cleft syndrome type 1 129900 endocrine–cerebroosteodysplasia syndrome 612651 ick focal dermal hypoplasia 305600 porcn frontonasal dysplasia 136760 alx3, alx4, alx1 fryns microphthalmia syndrome 600776 fryns syndrome 229850 genitopatellar syndrome 606170 kat6b hemifacial microsomia 164210 hypothalamic hamartomas 241800 johnson neuroectodermal syndrome 147770 juvenile myoclonic epilepsy 254770 kabuki syndrome 147920 kmt2d, kdm6a kallmann syndrome 308700 anos1 lenz–majewski hyperostotic dwarfism 151050 ptdss1 lissencephaly 3 611603 tuba1a marden–walker syndrome 248700 piezo2 masa syndrome 303350 l1cam microhydranencephaly 605013 nde1 mowat–wilson syndrome 235730 zeb2 ndh syndrome 610199 glis3 oculoauriculofrontonasal syndrome 601452 oculocerebrocutaneous syndrome 164180 oculodentodigital dysplasia 164200 gja1 optiz–kaveggia syndrome 305450 med12 otopalatodigital syndrome 2 304120 flna periventricular heterotopia x‐linked 300049 flna perlman syndrome 267000 dis3l2 pitt–hopkins syndrome 610954 tcf4 polycystic liver disease 174050 proteus syndrome 176920 akt1 pseudotrisomy 13 264480 retinal cone dystrophy 1 180020 some forms of retinitis pigmentosa 268000 robinow syndrome 268310 ror2 rubinstein–taybi syndrome 180849 crebbp sakoda complex 610871 schinzel–giedion syndrome 269150 setbp1 split-hand/foot malformation 3 246560 spondyloepiphyseal dysplasia congenita 183900 col2a1 thanatophoric dysplasia 187600 fgfr3 townes–brocks syndrome 107480 sall1, dact1 tuberous sclerosis 191100 tsc1, tsc2 vater association 192350 ven den ende–gupta syndrome 600920 scarf2 visceral heterotaxy 606325 walker–warburg syndrome 236670 warburg micro syndrome 615663 rab3gap1 x‐linked congenital hydrocephalus 307000 l1cam x‐linked lissencephaly 300067 dcx young–simpson syndrome 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. 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 made possible the understanding of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell. 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. 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.