Ciliopathy

Ciliopathies are a group of genetically diverse disorders caused by defects in the structure or function of the primary cilium, a highly specialized and evolutionarily conserved organelle found in nearly all eukaryotic cells.^[1] The primary cilium plays a central role in regulating signal transduction and making it essential for numerous developmental and physiological processes.^[2]

Because of the widespread presence of primary cilia in different tissues, dysfunction can lead to a broad spectrum of clinical features. Syndromic ciliopathies, such as Bardet-Biedl syndrome (BBS), typically involve multiple organ systems, including the retina, kidneys, central nervous system, and skeletal system^[1] These manifestations highlight the importance of cilia in embryonic development, sensory perception, and tissue homeostasis.^[3]

The genetic basis of ciliopathies is complex, with significant allelic heterogeneity and pleiotropy, meaning the same gene may cause different disorders, while different mutations can result in overlapping clinical features. Such variability makes genotype-phenotype correlation particularly challenging.^[1][4] Advances in genetic technologies, such as expression quantitative trait locus (eQTL) analysis, are helping to clarify the molecular mechanisms that drive these diseases. While progress has been made in understanding ciliogenesis and the molecular pathways involved, therapeutic development is still in its early stages. Gene therapy and other molecular approaches hold promise but must overcome several scientific and technical barriers before they can be widely implemented.^[1]

Primary cilia, which are found on nearly all cell types, function as sensory structures and integrate signals from the environment. When these functions are compromised, it can lead to serious diseases such as polycystic kidney disease, Bardet-Biedl syndrome, Joubert syndrome, and primary ciliary dyskinesia.^[3] Even proteins that are not directly localized to the cilia, such as XPNPEP3—which is associated with mitochondria—can cause ciliopathies by affecting proteins essential to ciliary function.^[1]

In the 1990s, important advances were made in understanding the significance of cilia.^[5] Ciliary defects were identified in genetic disorders such as nephronophthisis and primary ciliary dyskinesia, and it became clear that abnormalities in ciliary structure and transport mechanisms could explain the broad, multi-organ effects observed in patients with ciliopathies.^[1][3]

Although our understanding of the role of cilia in developmental biology and disease has grown considerably over the past decade, the mechanisms behind their function in many tissues remain incompletely described. Current research is particularly focused on how disruptions in intraflagellar transport, signal reception, and cilia-associated protein complexes contribute to the pathogenesis of ciliopathies.^[3][4]