The contribution of primary cilia to the pathogenesis of retinal neurodegenerative diseases is an active area of research. Over 120 genes have been identified as being associated with retinal ciliopathies (Supplementary Table 1), with new genes constantly being identified. Most of these genes are related to primary cilia assembly. More specifically, transition zone/basal body genes participate in cilium organization and maintenance of transition fibers and the basal body, which act as anchors for the cilium to the cell membrane (Yuan et al. 2015; Tereshko et al. 2022). The transport of proteins and other molecules along the ciliary axoneme relies on IFT genes. Centrosome/pericentriolar material genes are involved in ciliogenesis and cilia stability. Ciliary membrane genes contribute to the structure and function of the ciliary membrane itself (Fig. 2A).

Fig. 2

Genes associated with retinal ciliopathies. A Gene Ontology enrichment analysis of retinal ciliopathy genes shows that most of these genes belong to 7 functional groups. B A functional interaction network obtained from the reactome (https://reactome.org/) was built based on the interactions between retinal ciliopathy proteins

Importantly, some proteins may have multiple subcellular localizations within cilia, performing distinct functions in different parts of the organelle. Additionally, the proteins encoded by these genes are directly responsible for changes mediated by ciliopathies. All these proteins are linked to each other in a global functional interaction network (Fig. 2B); thus, the impact of a ciliopathy mutation is not restricted to a specific gene product. It also affects the interacting partners and, as a result, can impact the activity of a whole subnetwork. Instead of focusing on particular genes or loci implicated in ciliopathies, functional interaction-based analyses highlight the connections that are most changed by the disease state, helping to uncover higher-order relationships in the genetic architecture of ciliopathies.

Retinal ciliopathies can be inherited through three distinct inheritance patterns: X-linked recessive, autosomal recessive, or autosomal dominant. Since axoneme structure is shared between sperm flagella and photoreceptor cilia, individuals diagnosed with X-linked ciliopathies usually exhibit abnormalities in the morphology of sperm tails as well as impaired sperm motility. Furthermore, conditions can be categorized as nonsyndromic or syndromic. Nonsyndromic retinal ciliopathies, such as LCA and RP, are generally characterized by localized retinal defects, lacking the accompanying systemic symptoms observed in syndromic variants. Syndromic retinal ciliopathies exhibit retinal involvement as well as other systemic or organ-specific characteristics. These additional attributes have the potential to impact several physiological systems, resulting in the manifestation of a group of distinguishing characteristics (syndromic), such as BBS, JBTS and AS.

Nonsyndromic retinal ciliopathiesRetinitis pigmentosa (RP, MIM 268000)

RP is an inherited retinal disorder characterized by the gradual loss of photoreceptor cells that leads to irreversible visual impairment (Verbakel et al. 2018). Individuals diagnosed with RP typically first exhibit symptoms of nyctalopia, followed by progressive loss of peripheral vision, ultimately leading to severe visual impairment or complete blindness. The clinical presentation of RP exhibits variability depending on the age at which symptoms first appear and the speed at which the degeneration of photoreceptor cells occurs. The estimated frequency of RP is approximately 1 in 3500–4000 individuals. To date, around 200 genes have been identified as being linked to RP (Shivanna et al. 2019). Among these, a minimum of 18 genes are responsible for encoding proteins that localize within the cilia of photoreceptor cells. Moreover, these genes are connected to a specific inheritance pattern: specifically, genes such as ARL6, BBS1, BBS9, C2ORF71, C8ORF37, CLRN1, FAM161A, MAK, TTC8, TULP1, USH2A, and CEP290 are linked to autosomal recessive RP; RP1, TOPORS, and RP1L1 cause autosomal dominant RP; and X-linked RP is connected to mutations in genes such as OFD1, RP2, and RPGR. The proteins encoded by these genes vary in function, and mutations at these levels alter the structure or signaling pathways of primary cilia, resulting in the demise of photoreceptor cells and vision loss.

Leber congenital amaurosis (LCA, MIM 204000)

Leber congenital amaurosis (LCA) is commonly characterized by an extremely early onset of visual impairment, nystagmus, and amaurotic pupils (Huang et al. 2021). LCA is a significant contributor to childhood blindness, accounting for approximately 20% of cases. LCA is considered an autosomal recessive, genetically heterogeneous condition. The discovery of de novo mutations in CRX, OTX2, and IMPDH1, which are associated with LCA, has sparked a discussion on the potential presence of dominant inheritance patterns in certain cases of LCA (Rivolta et al. 2001; Bowne et al. 2006; Zou et al. 2013; Roger et al. 2014). Approximately 75% of LCA cases can be attributed to particular mutations (Supplementary Table 1). The disease-causing mechanisms that are commonly observed include phototransduction (GUCY2D, AIPL1, RD3, and KCNJ13), retinoids (RPE65, LRAT, and RDH12), ciliary transportation (LCA5, CEP290, RPGRIP1, SPATA7, TULP1, and IQCB1/NPHP5), photoreceptor morphogenesis (CRX, CRB1, GDF6, and PRPH2), guanine synthesis (IMPDH1), and photoreceptor differentiation (OTX2). The underlying mechanism responsible for the LCA phenotype associated with recently discovered mutations in USP45 (LCA type 19) and other genes remains a subject of debate, requiring further investigation.

Cone-rod dystrophy (CORD, MIM 120970)

There are more than 30 distinct types of cone-rod dystrophies that can be classified as recessive, dominant, or X-linked (Tsang and Sharma 2018). One of the distinguishing features of these pathologies is the presence of retinal pigment deposits that are observable during fundus examination. These deposits are primarily concentrated in the macular region. In contrast to retinitis pigmentosa (RP), which is characterized by the initial degeneration of rod photoreceptors followed by the subsequent loss of cone photoreceptors, CORD exhibits a reverse pattern of progression.

The pathogenesis of CORD involves four primary causative genes: ABCA4, CRX, GUCY2D, and RPGR (Birtel et al. 2018). ABCA4, a protein involved in the transport of retinaldehyde, accounts for approximately 30 to 60% of autosomal recessive CORDs, with mutations at this level leading to impaired cone and rod photoreceptor function. CRX and GUCY2D are factors that play crucial roles in the development of photoreceptor cells and the phototransduction pathway, respectively; mutations in these proteins lead to impaired photoreceptor function and degeneration and are responsible for a significant number of reported cases of autosomal-dominant CORDs. Mutations in RPGR, on the other hand, lead to disruptions in ciliary function in photoreceptor cells and cause degeneration of cones and rods. These mutations are involved in approximately two-thirds of cases of X-linked retinitis pigmentosa (RP) and an undetermined fraction of X-linked CORDs. In addition, mutations in genes such as RP1 and CEP290 have been linked to certain occurrences of CORD (Supplementary Table 1).

Syndromic retinal ciliopathiesSenior–Løken Syndrome (SLS, MIM 266900)

Senior–Løken Syndrome (SLS) is an autosomal-recessive disorder characterized by the presence of juvenile nephronophthisis, retinal degeneration that results in blindness, and the eventual development of end-stage renal disease (Tsang et al. 2018). Mutations in at least 13 genes have been reported to lead to SLS (Salomon et al. 2008). Most NPHP proteins have been reported to localize to the base or axoneme of primary cilia as well as to the connecting cilium of the photoreceptor (Supplementary Table 1). The presence of germline deletions in Nphp8 and Nphp12 has been found to result in embryonic lethality. Several animal germline knockouts have been produced, specifically targeting the NPHP1, -3, -4, -5, -6, -7, and -14 genes.

However, none of these loss-of-function rodent models have successfully recapitulated the entire phenotype of SLS observed in humans. Since various animals exhibit distinct processes of disease onset and the properties of organs vary according to their evolutionary history, animal disease models can have restricted or limited use. In vitro disease models can be used as another alternative for ciliopathies. A recent study employed dermal fibroblasts from patients with NPHP5-LCA, retinal pigment epithelium (RPE) cells and retinal organoids from patient-derived induced pluripotent stem cells (iPSCs) to develop a 3D culture system mimicking the in vivo model (Kruczek et al. 2022). The investigation revealed that retinal organoids displayed aberrant elongated cilia and decreased quantities of CEP290. Additionally, the photoreceptors within these patient organoids exhibited compromised protein localization and abnormal extension of outer segments.

Bardet–Biedl Syndrome (BBS, OMIM 209900)

Bardet–Biedl Syndrome (BBS) is a rare autosomal-recessive disorder characterized by a combination of clinical features, including retinal degeneration, obesity, postaxial polydactyly, learning impairments, renal involvement, and male hypogenitalism. BBS is genetically diverse, and 18 genes (BBS1-18) have been characterized to date. Among these genes, BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBS18 have been shown to form a stable complex known as the “BBSome.” The BBSome complex functions as an adaptor between cargo and the IFT complex and directs the movement of over one hundred proteins from the OS to the IS of photoreceptors. This mechanism effectively prevents the excessive accumulation of these proteins in the OS and maintains its structural integrity. Furthermore, the absence of specific functional subunits of the BBSome leads to the malformation of the OS.

Approximately 70–80% of cases can be attributed to mutations in established BBS genes. Due to limited knowledge regarding the necessity of the BBSome during eye development and maturation, no definitive association has been established between the genotype and clinical manifestations of BBS for the majority of reported variants. Multiple studies have indicated the presence of a less severe phenotype when certain mutations in BBS genes are observed (M’hamdi et al. 2014; Berezovsky et al. 2012).

Through the examination of BBS12 mouse models, researchers discovered that the initiation of an unfolded protein response, induced by protein accumulation in the endoplasmic reticulum of photoreceptors, can stimulate apoptosis and lead to degeneration of the retina (Mockel et al. 2012).

Joubert Syndrome (JBTS, MIM 213300)

Joubert Syndrome (JBTS) is an autosomal-recessive disorder characterized by symptoms such as episodic hyperpnea, global developmental delays, ataxia, and aberrant eye movements. Currently, pathogenic variations in more than 40 genes have been associated with JBTS. Among these genes, most exhibit autosomal recessive inheritance, while one gene is X-linked (Parisi and Glass 1993; Dong et al. 2023). The most common genes were AHI1, CC2D2A, CEP290, CPLANE1, CSPP1, INPP5E, KIAA0586, MKS1, NPHP1, RPGRIP1L, TMEM67, and TMEM216 (Supplementary Table 1). Less common genes included ARL13B, B9D1, C2CD3, CEP104, CEP120, KIAA0556, PDE6D, POC1B, TCTN1, TCTN3, TMEM138, TMEM231, TMEM237, CHD7 and OFD1 (X-linked) (Wang et al. 2018).

Alström Syndrome (ALMS, MIM 203800)

Alström Syndrome is an autosomal-recessive monogenic disease caused by homozygous or compound heterozygous variants in the ALMS1 gene. The clinical manifestation of ALMS is characterized by a variety of clinical features, including retinal degeneration, obesity, sensorineural hearing loss, insulin resistance, and progressive hepatic and renal dysfunction. The ALMS1 gene consists of 23 exons and encodes a protein of 4169 amino acids. The expression of ALMS1 is observed in a broad range of tissues, and it is localized in the centrosomes as well as at the base of cilia. To date, more than 230 mutations in the ALMS1 gene have been identified as causative factors for various diseases (Marshall et al. 2015). A significant proportion (96%) of the observed mutations are classified as nonsense and frameshift variants, which are anticipated to result in the premature truncation of the protein. The precise function of the protein derived from the ALMS1 gene remains incompletely elucidated; however, it has been implicated in various biological processes, including ciliary function, regulation of the cell cycle, organization of microtubules, and intracellular transport.

ALMS1 mutations account for the preponderance of Alström syndrome cases. However, there are certain individuals who exhibit clinical symptoms of Alström syndrome, but the genotype–phenotype correlation in these cases remains unidentified. Researchers continue to investigate the condition in an effort to identify additional genes or genetic factors that may play a role in its development.

Usher Syndrome (USH, OMIM 276901)

Usher Syndrome is an autosomal-recessive syndromic ciliopathy characterized by congenital hearing impairment and the gradual development of retinitis pigmentosa in adulthood. Three distinct clinical types of Usher syndrome (USH1, USH2 and USH3) have been classified according to the severity of hearing loss, the age at which retinitis pigmentosa develops, and the presence or absence of vestibular response (Delmaghani and El-Amraoui 2022).

USH1 is the most severe subtype and is characterized by severe to profound congenital hearing loss, balance problems, and early-onset retinitis pigmentosa (RP). Genes associated with USH1 include MYO7A, CDH23, PCDH15, USH1C, USH1G, CIB2 (USH1J), and several others (Supplementary Table 1). USH2 is the most frequent subtype and is characterized by moderate to severe congenital hearing loss and retinitis pigmentosa (RP) but not vestibular dysfunction. The most common gene associated with USH2 is USH2A, accounting for a majority of cases. Other genes include GPR98 (PCDH15), DFNB31, ADGRV1 (USH2C), and WHRN. USH3 is the rarest form and is characterized by progressive hearing loss and retinitis pigmentosa (RP) but not vestibular dysfunction. Usher syndrome is caused by mutations in the CLRN1 gene, which is thought to play a role in the development and maintenance of photoreceptor cells and inner ear hair cells. Cases that do not fit into the established criteria for USH1, USH2, or USH3 are defined as atypical Usher syndrome (atypical USH). Pathogenic variants in many USH genes associated with atypical USH have been reported, including MYO7A, USH2A, CDH23, ADGRV1, CEP250, CEP78, and ABHD12.

Mutations in ADGRV1 and CIB2 have been linked to three separate subtypes of Usher syndrome. The two genes encode two proteins from independent protein families, adhesion G protein-coupled receptor (ADGRV1) and Ca2+- and integrin-binding protein 2 (CIB2). Interestingly, the comparison of the protein interactomes of CIB2 and ADGRV1 demonstrated a significant overlap in their interaction partners. Out of the 386 proteins identified as interaction partners of CIB2, 270 proteins have already been recognized as binding partners of ADGRV1 (Linnert et al. 2023; Knapp et al. 2022).

Furthermore, the interaction between CIB2 and ADGRV1 within a broader ciliary network that is also associated with USH, BBS, and specific forms of LCA (Fig. 2B) provides compelling evidence for shared molecular pathomechanisms underlying different syndromes (Linnert et al. 2023). This finding presents an opportunity to identify common therapeutic targets that can address the underlying defects in patients affected by these ciliopathies, regardless of the specific mutations involved.

Meckel–Gruber Syndrome (MKS, MIM 249000)

Meckel–Gruber Syndrome is an autosomal-recessive condition typically characterized by three symptoms: cerebral protrusion, cystic renal anomalies and polydactyly. The syndrome can also cause problems with the development of the eyes and other facial features.

To date, 17 genes have been identified as causative factors for MKS (Supplementary Table 1) (Hartill et al. 2017). Mutations in the MKS1 gene have been identified as the causative factor in approximately 7% of all MKS cases. Notably, these mutations account for approximately 70% of MKS cases specifically within the population of Finland (Hartill et al. 2017).

MKS cases display a notable degree of clinical overlap with JBTS, and at least 10 mutations (MKS1, TMEM216, TMEM67, CEP290, CC2D2A, NPHP3, TCTN2, B9D1, B9D2, and TMEM231) have been identified in both diseases.