Ciliopathy

Ciliopathy
Eukaryotic cilium
Specialty	Medical genetics

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. 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

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

• 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.^[9]

Phenotypes sometimes associated with ciliopathies can include:^[8]

• Anencephaly
• Breathing abnormalities
• Cerebellar vermis hypoplasia
• Diabetes
• Exencephaly
• Eye movement abnormalities
• Hydrocephalus
• Hypoplasia of the corpus callosum
• Hypotonia
• Infertility
• Cognitive impairment/defects
• Obesity^[10]
• 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.^[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:

• Chemosensation abnormalities,^[13] typically via ciliated epithelial cellular dysfunction.^[1]
• Defective thermosensation or mechanosensation,^[14] often via ciliated epithelial cellular dysfunction.^[1]
• Cellular motility dysfunction^[13]
• Issues with displacement of extracellular fluid^[13]
• Paracrine signal transduction abnormalities^[1][13]

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

• 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.^[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

"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

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

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

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

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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External links

• The Ciliary Proteome Web Page at Johns Hopkins Archived 29 April 2019 at the Wayback Machine