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Ciliopathy

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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.

Ciliopathy
Eukaryotic cilium
SpecialtyMedical genetics Edit this on Wikidata

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. For example, the discovery of the role of cilia in embryonic development, identification of ciliary defects in genetic disorders such as Polycystic kidney disease, Bardet–Biedl syndrome and Primary ciliary dyskinesia.[5][6] 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.[7]

Signs and symptoms

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A wide variety of symptoms are potential clinical features of ciliopathy. The signs most exclusive to a ciliopathy, in descending order of exclusivity, are:[8]: 138 

A case with polycystic ovary syndrome, multiple subcutaneous cysts, renal function impairment, Caroli disease and liver cirrhosis due to ciliopathy has been described.[9]

Phenotypes sometimes associated with ciliopathies can include:[8]

Pathophysiology

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"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.[11]

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.[12]

Dysfunctional cilia can lead to:

In organisms of normal health, cilia are critical for:[15]

Genetics

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"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.[16]

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."[10]

Additionally, clinical presentations of patients with identical mutation can differ, suggesting the role of genetic modifiers.[17]

As of 2017, 187 ciliopathy associated genes have been confirmed, while the roles of further 241 candidate genes are still being investigated.[18]

A common way to identify ciliopathies such as ADPKD and ARPKD which have known genetic causes, is through linkage analysis direct mutation screening.[19] Other techniques, such as gene panels and whole-exome sequencing and whole genome sequencing can also be used to provide distinct advantages.[19][20] Gene panels analyse specific sets of genes and can be more comprehensive than single gene or direct mutation screening. Whole-exome/genome sequencing can screen for heterozygous carriers, and detect novel/rare variations.[19][21]

Mutations in the PKD1 and PKD2 genes which encode for polycystin-1 and polycistin-2 respectively are known to be causes of ADPKD, a ciliopathy that presents with the formation and growth of cysts in the kidneys, leading to renal failure.[22]

List of ciliopathies

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"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.[8]

Known ciliopathies

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Condition OMIM Gene(s) Systems/organs affected
Alström syndrome[8][1] 203800 ALMS1
Asphyxiating thoracic dysplasia (Jeune syndrome)[8][23] 208500
Bardet–Biedl syndrome[8][7][10] 209900 BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12
Ellis–van Creveld syndrome[23] 225500 EVC, EVC2
Joubert syndrome[8][10] 213300 INPP5E, TMEM216, AHI1, NPHP1, CEP290, TMEM67, RPGRIP1L, ARL13B, CC2D2A, BRCC3 Brain
Leber congenital amaurosis[23] 204000 GUCY2D, RPE65
McKusick–Kaufman syndrome[23] 236700 MKKS
Meckel–Gruber syndrome[8][10][24] 249000 MKS1, TMEM67, TMEM216, CEP290, RPGRIP1L, CC2D2A Liver, heart, bone
Nephronophthisis[8][7][10] 256100 NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L Kidney
Orofaciodigital syndrome 1[1][7] 311200 OFD1
Polycystic kidney disease[8][7] (ADPKD and ARPKD)[25] 173900 PKD1, PKD2, PKHD1 Kidney
Primary ciliary dyskinesia (Kartagener syndrome)[8] 244400 DNAI1, DNAH5, TXNDC3, DNAH11, DNAI2, KTU, RSPH4A, RSPH9, LRRC50
Senior–Løken syndrome[7] 266900 NPHP1, NPHP4, IQCB1, CEP290, SDCCAG8 Eye
Sensenbrenner syndrome (cranioectodermal dysplasia)[23] 218330 IFT122
Short rib–polydactyly syndrome[23] 613091 DYNC2H1
? ? IFT88 Novel form of congenital anosmia, reported in 2012[26]

Likely ciliopathies

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Condition OMIM Gene(s) Systems/organs affected
Acrocallosal syndrome[23] 200990 KIF7, GLI3
Acromelic frontonasal dysostosis[23] 603671 ZSWIM6
Arima syndrome[23] 243910
Biemond syndrome[23] 113400
COACH syndrome[23] 216360 TMEM67, CC2D2A, RPGRIP1L
Conorenal syndrome[27][23] 266920
Greig cephalopolysyndactyly syndrome[23] 175700 GLI3
Hydrolethalus syndrome[23] 236680 HYLS1
Johanson–Blizzard syndrome[23] 243800 UBR1
Mohr syndrome (oral-facial-digital syndrome type 2)[23] 252100
Neu–Laxova syndrome[23] 256520 PHGDH, PSAT1, PSPH
Opitz G/BBB syndrome[23] 300000 MID1
Pallister–Hall syndrome[23] 146510 GLI3
Papillorenal syndrome[23] 120330 PAX2
Renal–hepatic–pancreatic dysplasia[23] 208540 NPHP3
Varadi–Papp syndrome (oral-facial-digital syndrome type 6)[23] 277170

Possible ciliopathies

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Condition OMIM Gene(s) Systems/organs affected
Acrofacial dysostosis[23]
Acrofrontofacionasal dysostosis 2[23] 239710
Adams–Oliver syndrome[23] 100300 ARHGAP31, DOCK6, RBPJ, EOGT, NOTCH1, DLL4
Asplenia with cardiovascular anomalies (Ivemark syndrome)[23] 208530
Autosomal recessive spastic paraplegia[23]
Barakat syndrome (HDR syndrome)[23] 146255 GATA3
Basal cell nevus syndrome[23] 109400 PTCH1, PTCH2, SUFU
Branchio‐oculo‐facial syndrome[23] 113620 TFAP2A
C syndrome (Opitz trigonocephaly)[23] 211750 CD96
Carpenter syndrome[23] 201000 RAB23
Cephaloskeletal dysplasia (microcephalic osteodysplastic primordial dwarfism type 1)[23] 210710 RNU4ATAC
Cerebrofaciothoracic dysplasia[23] 213980 TMCO1
Cerebrofrontofacial syndrome (Baraitser–Winter syndrome)[23] 243310 ACTB
Cerebrooculonasal syndrome[23] 605627
Autosomal recessive spastic ataxia of Charlevoix-Saguenay[23] 270550 SACS
Chondrodysplasia punctata 2[23] 302960 EBP
Choroideremia[23] 303100 CHM
Chudley–McCullough syndrome[23] 604213 GPSM2
C‐like syndrome[23] 605039 ASXL1
Coffin–Siris syndrome[23] 135900 ARID1B, SOX11, ARID2
Cohen syndrome[23] 216550 VPS13B
Craniofrontonasal dysplasia[23] 304110 EFNB1
Dysgnathia complex[23] 202650
Ectrodactyly–ectodermal dysplasia–cleft syndrome type 1[23] 129900
Endocrine–cerebroosteodysplasia syndrome[23] 612651 ICK
Focal dermal hypoplasia[23] 305600 PORCN
Frontonasal dysplasia[23] 136760 ALX3, ALX4, ALX1
Fryns microphthalmia syndrome[23] 600776
Fryns syndrome[23] 229850
Genitopatellar syndrome[23] 606170 KAT6B
Hemifacial microsomia[23] 164210
Hypothalamic hamartomas[23] 241800
Johnson neuroectodermal syndrome[23] 147770
Juvenile myoclonic epilepsy[28] 254770
Kabuki syndrome[23] 147920 KMT2D, KDM6A
Kallmann syndrome[23] 308700 ANOS1
Lenz–Majewski hyperostotic dwarfism[23] 151050 PTDSS1
Lissencephaly 3[23] 611603 TUBA1A
Marden–Walker syndrome[8][23] 248700 PIEZO2
MASA syndrome[23] 303350 L1CAM
Microhydranencephaly[23] 605013 NDE1
Mowat–Wilson syndrome[23] 235730 ZEB2
NDH syndrome[23] 610199 GLIS3
Oculoauriculofrontonasal syndrome[23] 601452
Oculocerebrocutaneous syndrome[23] 164180
Oculodentodigital dysplasia[23] 164200 GJA1
Optiz–Kaveggia syndrome[23] 305450 MED12
Otopalatodigital syndrome 2[23] 304120 FLNA
Periventricular heterotopia X‐linked[23] 300049 FLNA
Perlman syndrome[23] 267000 DIS3L2
Pitt–Hopkins syndrome[23] 610954 TCF4
Polycystic liver disease[8] 174050
Proteus syndrome[23] 176920 AKT1
Pseudotrisomy 13[23] 264480
Retinal cone dystrophy 1[23] 180020
Some forms of retinitis pigmentosa[8][29][23] 268000
Robinow syndrome[23] 268310 ROR2
Rubinstein–Taybi syndrome[23] 180849 CREBBP
Sakoda complex[23] 610871
Schinzel–Giedion syndrome[23] 269150 SETBP1
Split-hand/foot malformation 3[23] 246560
Spondyloepiphyseal dysplasia congenita[23] 183900 COL2A1
Thanatophoric dysplasia[23] 187600 FGFR3
Townes–Brocks syndrome[23] 107480 SALL1, DACT1
Tuberous sclerosis[23] 191100 TSC1, TSC2
VATER association[23] 192350
Ven den Ende–Gupta syndrome[23] 600920 SCARF2
Visceral heterotaxy[23] 606325
Walker–Warburg syndrome[23] 236670
Warburg Micro syndrome[23] 615663 RAB3GAP1
X‐linked congenital hydrocephalus[23] 307000 L1CAM
X‐linked lissencephaly[23] 300067 DCX
Young–Simpson syndrome[23] 603736 KAT6B

History

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In 1674–1677, the Dutch scientist Antonie van Leeuwenhoek changed humanity's perspective on the world with his discovery of "animalcules" in rainwater, along with their tiny appendages known as cilia today. It was marked as the first recorded observation of single-celled organisms and their locomotive structures.[30]

In the late 19th century, Karl Ernst von Baer's groundbreaking work in embryonic development laid the foundation for modern developmental biology.[31] Through meticulous observations, von Baer provided invaluable insights into tissue and organ formation during development, including the early stages of embryogenesis and the development of cilia-bearing tissues.[32] While von Baer may not have fully appreciated the significance of cilia at the time, his observations likely included their presence in embryonic tissues. Cilia - crucial for cell signaling, tissue development, and left-right asymmetry, are now recognized as ancient organelles with essential roles in development.[33] Von Baer's concept of embryonic recapitulation, despite refinement, underscores the evolutionary conservation of developmental processes, including ciliary function. Today, von Baer's legacy inspires ongoing research into embryology and developmental biology, particularly in understanding ciliary biology and its relevance to ciliopathies, where defects in ciliary structure or function lead to developmental disorder.[34]

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.[35] 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."[11]

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.[36] 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.[8]

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.[7]

References

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