Ciliopathy

Since cilia are found in many different types of cells and organs, the body will be affected if there is an error or dysfunction. When the cilia do not function properly, multiple symptoms commonly occur, such as:

• Retinal degeneration
• Obesity
• Renal dysfunction
• Hepatic abnormalities
• Diabetes
• Hypertension
• Polydactyly
• Hearing impairment
• Skeletal anomalies
• Congenital heart defects
• Anosmia
• Abnormal heart size
• Infertility
• Intellectual disabilitites

Although significant progress has been made in understanding cilia and their role in disease, many aspects remain unexplored. Ongoing research is crucial to uncover the underlying mechanisms of ciliopathies and to develop effective therapeutic strategies.{{Cite book |last1=Yealland |first1=G. |last2=Jevtic |first2=M. |last3=Eckardt |first3=K.-U. |last4=Schueler |first4=M. |title=Cilia: From Mechanisms to Disease - Part B |date=2023 |chapter=Modeling ciliopathies in patient-derived primary cells |chapter-url=https://pubmed.ncbi.nlm.nih.gov/37164535 |series=Methods in Cell Biology |volume=176 |pages=139–158 |doi=10.1016/bs.mcb.2023.02.016 |issn=0091-679X |pmid=37164535|isbn=978-0-443-18588-5 }}{{Cite journal |last1=Vrabič |first1=N. |last2=Fakin |first2=A. |last3=Tekavčič Pompe |first3=M. |date=Oct 2024 |title=Spectrum and frequencies of extraocular features reported in CEP290-associated ciliopathy- a systematic review |url=https://pubmed.ncbi.nlm.nih.gov/39213781 |journal=Journal Francais d'Ophtalmologie |volume=47 |issue=8 |pages=104232 |doi=10.1016/j.jfo.2024.104232 |issn=1773-0597 |pmid=39213781|hdl=20.500.12556/RUL-161731 |hdl-access=free }}

Cilia are microscopic, hair-like structures that extend from the surface of nearly all mammalian cells. They are composed of complex protein structures and play a crucial role in various cellular functions, including movement and signal transduction.{{Cite journal |last1=Arora |first1=Shashank |last2=Rana |first2=Mausam |last3=Sachdev |first3=Ananya |last4=D'Souza |first4=Jacinta S. |date=2023 |title=Appearing and disappearing acts of cilia |journal=Journal of Biosciences |volume=48 |issue=1 |pages=8 |doi=10.1007/s12038-023-00326-6 |issn=0973-7138 |pmc=10005925 |pmid=36924208}}

Cilia are categorized into two main structural subtypes based on the organization of their microtubule axoneme: motile and non-motile (primary) cilia. Motile cilia are typically structured in a 9+2 arrangement, consisting of nine outer microtubule doublets surrounding a central pair of microtubules. This structure is specialized for movement, enabling functions such as fluid transport across epithelial surfaces, cell motility, and propulsion of spermatozoa.{{Cite journal |last1=Wallmeier |first1=Julia |last2=Nielsen |first2=Kim G. |last3=Kuehni |first3=Claudia E. |last4=Lucas |first4=Jane S. |last5=Leigh |first5=Margaret W. |last6=Zariwala |first6=Maimoona A. |last7=Omran |first7=Heymut |date=2020-09-17 |title=Motile ciliopathies |url=https://pubmed.ncbi.nlm.nih.gov/32943623 |journal=Nature Reviews. Disease Primers |volume=6 |issue=1 |pages=77 |doi=10.1038/s41572-020-0209-6 |issn=2056-676X |pmid=32943623}}{{Cite journal |last1=Goetz |first1=Sarah C. |last2=Anderson |first2=Kathryn V. |date=May 2010 |title=The primary cilium: a signalling centre during vertebrate development |journal=Nature Reviews. Genetics |volume=11 |issue=5 |pages=331–344 |doi=10.1038/nrg2774 |issn=1471-0064 |pmc=3121168 |pmid=20395968}}

In contrast, primary (non-motile) cilia display a 9+0 arrangement, where nine outer microtubule doublets are present without a central pair. Rather than generating movement, these cilia serve as cellular antennae, playing crucial roles in sensory perception, intracellular signaling, and regulation of developmental pathways, including organogenesis. Primary cilia function mainly as sensory organelles, involved in signal transduction and the maintenance of cellular homeostasis.{{Cite journal |last1=Focșa |first1=Ina Ofelia |last2=Budișteanu |first2=Magdalena |last3=Bălgrădean |first3=Mihaela |date=Sep 2021 |title=Clinical and genetic heterogeneity of primary ciliopathies (Review) |journal=International Journal of Molecular Medicine |volume=48 |issue=3 |pages=176 |doi=10.3892/ijmm.2021.5009 |issn=1791-244X |pmc=8354309 |pmid=34278440}}

This structural distinction is fundamental to understanding the diverse biological functions and pathologies associated with ciliopathies.

Ciliopathies are genetically heterogeneous disorders that arise due to mutations in genes associated with the structure and function of cilia. A unique feature of these conditions is that the same gene can be involved in different diseases, and that different genes can lead to similar phenotypes.{{Cite journal |last1=Mill |first1=Pleasantine |last2=Christensen |first2=Søren T. |last3=Pedersen |first3=Lotte B. |date=Sep 2023 |title=Primary cilia as dynamic and diverse signalling hubs in development and disease |journal=Nature Reviews. Genetics |volume=24 |issue=7 |pages=421–441 |doi=10.1038/s41576-023-00587-9 |issn=1471-0064 |pmc=7615029 |pmid=37072495}} For example, mutations in certain genes have been linked to both Meckel–Gruber syndrome and Bardet–Biedl syndrome, and in some patients carrying mutations in both, combined phenotypes have been observed that do not occur in either condition alone.

Because ciliopathy genes often function within interconnected developmental pathways, systems biologists are seeking to define gene modules—co-regulated sets of genes that drive specific biological outcomes.

Furthermore, significant phenotypic overlap has been documented among different ciliopathies, largely due to the fact that many of the involved genes affect primary cilia function. As a result, the same mutation can lead to different clinical presentations, suggesting that genetic modifiers (i.e., other genes that influence disease expression) play an important role in determining disease severity and organ involvement.

As of 2017, 187 genes had been confirmed to be directly associated with ciliopathies, with an additional 241 candidate genes still under investigation.

This genetic complexity makes molecular diagnosis both challenging and essential. For inherited ciliopathies such as autosomal dominant and autosomal recessive polycystic kidney disease (ADPKD and ARPKD), traditional methods like linkage analysis and targeted mutation screening have been used.

Modern approaches such as gene panels, exome sequencing, and whole genome sequencing are increasingly replacing traditional methods, as they enable the identification of both known and rare mutations and can detect heterozygous carriers in recessive disorders. These methods allow for broader detection of both common and rare mutations and are particularly useful for identifying heterozygous carriers in recessive ciliopathies. By providing a more comprehensive genetic profile, these tools enhance diagnostic precision and support the identification of novel ciliopathy- associated genes.

A classic example of a genetically defined ciliopathy is ADPKD, which is caused by mutations in PKD1 and PKD2, encoding polycystin-1 and -2, respectively. These proteins are essential for the mechanosensory function of cilia in the renal epithelium. Mutations result in defective signaling and cyst formation, which can eventually lead to kidney failure.

The discovery of cilia marked a pivotal moment in biological science. In the 1670s, Dutch microscopist Antonie van Leeuwenhoek described microscopic "animalcules" in rainwater, observing tiny, moving projections on their surfaces—structures that are now recognized as cilia. This was the first recorded observation of cellular appendages involved in locomotion and environmental sensing.{{Cite journal |last1=Modarage |first1=K. |last2=Malik |first2=S. A. |last3=Goggolidou |first3=P. |date=January 2022 |title=Molecular Diagnostics of Ciliopathies and Insights Into Novel Developments in Diagnosing Rare Diseases |journal=British Journal of Biomedical Science |volume=79 |pages=10221 |doi=10.3389/bjbs.2021.10221 |doi-access=free |issn=2474-0896 |pmc=8915726 |pmid=35996505 }}

Despite early recognition, the functional importance of cilia remained underappreciated for centuries. Non-motile, or primary cilia, were first described in 1898, but were largely dismissed as vestigial structures without biological significance. It was not until the advent of advanced microscopy and molecular genetics in the late 20th and early 21st centuries that the essential roles of cilia in development and disease became clear.

Today, primary cilia are understood as sensory organelles that coordinate diverse signaling pathways such as Hedgehog and Wnt, and are critical for tissue patterning, cellular differentiation, and organ development. Cilia function as cellular “antennae,” detecting mechanical, chemical, and thermal cues from the environment.

The modern era of ciliopathy research has been driven by advances in mammalian genetics. These have enabled the identification of mutations in cilia-related genes that underlie a wide spectrum of genetic disorders, now collectively referred to as ciliopathies. These include autosomal dominant and recessive polycystic kidney disease, nephronophthisis, Bardet–Biedl syndrome, Joubert syndrome, and others. The overlapping phenotypes of these diseases reflect the shared molecular architecture of cilia and their conserved roles across organ systems.

Foundational work in embryology by scientists such as Karl Ernst von Baer laid the conceptual groundwork for modern developmental biology. Although von Baer did not explicitly describe cilia, his meticulous observations of embryonic tissues likely included ciliated structures. His legacy continues to influence current research into the roles of cilia in early development, particularly in establishing left-right asymmetry and proper organ positioning.

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• [http://v3.ciliaproteome.org/cgi-bin/index.php The Ciliary Proteome Web Page at Johns Hopkins] {{Webarchive|url=https://web.archive.org/web/20190429061344/http://v3.ciliaproteome.org/cgi-bin/index.php |date=29 April 2019 }}

{{Other genetic disorders by mechanism}}

Category:Genetic diseases and disorders