Conserved Genetic Interactions between Ciliopathy Complexes Cooperatively Support Ciliogenesis and Ciliary Signaling

Abstract

Mutations in genes encoding cilia proteins cause human ciliopathies, diverse disorders affecting many tissues. Individual genes can be linked to ciliopathies with dramatically different phenotypes, suggesting that genetic modifiers may participate in their pathogenesis. The ciliary transition zone contains two protein complexes affected in the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP). The BBSome is a third protein complex, affected in the ciliopathy Bardet-Biedl syndrome (BBS). We tested whether mutations in MKS, NPHP and BBS complex genes modify the phenotypic consequences of one another in both C. elegans and mice. To this end, we identified TCTN-1, the C. elegans ortholog of vertebrate MKS complex components called Tectonics, as an evolutionarily conserved transition zone protein. Neither disruption of TCTN-1 alone or together with MKS complex components abrogated ciliary structure in C. elegans. In contrast, disruption of TCTN-1 together with either of two NPHP complex components, NPHP-1 or NPHP-4, compromised ciliary structure. Similarly, disruption of an NPHP complex component and the BBS complex component BBS-5 individually did not compromise ciliary structure, but together did. As in nematodes, disrupting two components of the mouse MKS complex did not cause additive phenotypes compared to single mutants. However, disrupting both Tctn1 and either Nphp1 or Nphp4 exacerbated defects in ciliogenesis and cilia-associated developmental signaling, as did disrupting both Tctn1 and the BBSome component Bbs1. Thus, we demonstrate that ciliary complexes act in parallel to support ciliary function and suggest that human ciliopathy phenotypes are altered by genetic interactions between different ciliary biochemical complexes.

Tectonic Proteins Are Important Players in Non-Motile Ciliopathies

“…Therefore, mutant tectonic proteins disrupt the functions of MKS/JBTS complexes and cause Meckel-Gruber syndrome, Joubert syndrome, as well as Oralfacial-digital syndrome. TCTN2, TCTN3, MKS1, B9D1, AHI1，NPHP1，NPHP4, and CC2D2A have been proved to interact with TCTN1, while TMEM67, TMEM216 and CEP290 can be the interactors of TCTN1 under some conditions [20,21,24,41]. Among all those molecules, TCTN2 and TCTN3 show strongest interactions with TCTN1, which is in accordance with the fact of being in one protein family [24].…”

“…In addition, TCTN2 and TCTN3 also have interactions with MKS1 as shown in Fig. 2 [21,41]. All three tectonic proteins have been proved to play an essential role in regulating ciliary membrane composition, ciliogenesis, neural patterning, and the Shh signaling pathway.…”

“…Different members of tectonic proteins display distinct roles in regulating the Shh pathway because the Shh pathway-related developmental abnormalies are found in mice with tectonics deletion. Tctn1 null mice present holoprosencephaly, heterotaxia, microphthalmia, and hindlimb polydactyly that resemble the phenotypes of mice with Shh signaling defects [20,41]. Except for these characteristics in Tctn1 -/-mice, additional phenotypes including cleft palate, ventricular septal defects and right-sided stomach are present in Tctn2 -/-mice [21].…”

Super-resolution microscopy reveals that disruption of ciliary transition-zone architecture causes Joubert syndrome

“…For example, in mice, compound mutation of genes encoding MKS and NPHP complex components synergistically disrupts ciliogenesis and Hedgehog developmental signaling 57 . Similarly, in C. elegans, mutation of individual MKS or NPHP complex genes does not disrupt ciliogenesis, but compound mutation of MKS and NPHP complex genes abrogate ciliary structure 22,57 . The overlapping localizations and functions of the NPHP and MKS complexes suggest that they have partially overlapping roles in controlling ciliogenesis and ciliary composition (Figure 6D).…”

Reply to: “Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis”

“…Such a mechanism is the one suggested in animal models of Meckel, Nephronophthisis and Bardet-Biedl syndromes [7] where all 3 complexes contribute synergistically to variability in ciliogenesis. The complexity of the interactions amongst different ciliary structures and their function remains a challenging field for researchers.…”