Outside of OFD and EVC, craniofacial features have not historically been considered among the primary diagnostic criteria for ciliopathies. However, increasing recognition of the role of cilia in regulating signaling transduction and cell migration during craniofacial development has turned attention to the face. With the understanding of ciliopathies growing, a phenotypic classification scheme is beginning to emerge. There is growing support for the proposition that ciliopathies are associated with a higher degree of phenotypic similarity than non-ciliopathies (Baker and Beales, 2009
). While diagnosis based on phenotypic presentation is impossible, a recent review defines and identifies nine core characteristics (retinitis pigmentosa, renal cystic disease, polydactyly, mental retardation, situs inversus, agenesis of the corpus callosum, Dandy-Walker malformation, posterior encephalocele and hepatic disease) that are more likely present in a ciliopathy rather than a disorder not caused by ciliary dysfunction (Baker and Beales, 2009
). In addition, less globally penetrant phenotypes, such as obesity, insulin resistance/diabetes, cardiovascular defects and skeletal anomalies, have also been reported in patients with ciliopathies (Baker and Beales, 2009
Beales and colleagues hypothesize that the greater number of these core features within any individual, the higher the likelihood of a ciliopathy. Using these core characteristics as criteria of a ciliopathy they profiled two disease databases (London Dysmorphology Database and OMIM) for syndromes that presented with some combination of the nine core characteristics. They identified 102 conditions with a unique combination of the core characteristics that are either known, or what they considered possible ciliopathies. When evaluating the disorders presented by Beales and colleagues as known, likely and potential ciliopathies, we find that approximately 30% of the disorders put forth are defined primarily by their craniofacial phenotype ( and ). Of those disorders, approximately 70% present with midfacial defects, specifically hypertelorism- the widening of the midface. Can midfacial dysmorphology be used as a hallmark of a craniofacial ciliopathy? Perhaps that link is a bit simplistic and premature at present, but given the relationship between cilia, important craniofacial signaling pathways and midfacial development, the appearance of midfacial defects in unclassified craniofacial syndromes should warrant the examination of ciliary genes in patients.
The prevalence of midfacial defects in known and potential ciliopathies is not very surprising given the established role of cilia in Shh and Wnt signal transduction. Indeed, deciphering ciliary regulation of these pathways will likely play a large part in our understanding of ciliary involvement in craniofacial patterning. It will be critical to understand, for example, if perturbed ciliary function gives rise primarily to Shh defects, Wnt defects or both. Evidence in both mouse and zebrafish models point to the disruption of both pathways in the developing face of ciliary mutants and morphants (Tobin et al., 2008
; Brugmann et al., 2010
). Given the differential observations of Shh and Wnt defects in different studies of ciliary mutants (Huang et al., 2009
; Lunt et al., 2009
), it remains to be seen if cilia are necessary for one pathway and producing secondary deficits in the other, or if the cilium truly acts a coordinating center for morphogenetic signaling response. Initial studies linking PDGF and cilia point to the latter possibility, suggesting a complexity of interplay between ciliary proteins and the coordinated regulation of multiple, key pathways.
An additional challenge will be to decipher the differential contributions of ciliary proteins. Available animal models used to study craniofacial features in ciliary mutants vary between IFT particles, IFT motor proteins, and basal body components (). In addition to differential effects on ciliogenesis (i.e. shortened vs. absent), suppression of different proteins can produce different phenotypes. For example, kif3a
knockout mice display severe craniofacial anomalies, however no such defects have been reported in bbs
knockout mice (Mykytyn et al., 2004
; Nishimura et al., 2004
; Fath et al., 2005
). In patients, the majority of disorders exhibiting primary craniofacial defects are caused by mutations in basal body proteins, such as OFD1, EVC or BBS. Sensenbrenner syndrome, a ciliopathy caused by a mutation in IFT122 (Walczak-Sztulpa et al., 2010
), is the only currently known human disorder caused by a defect in an IFT protein. Do basal bodies play a more prominent role in regulating craniofacial development in humans or have the defects of axonemal proteins just not be identified yet? To elucidate this question, it will be necessary to investigate several possibilities. First, the interaction of basal body proteins with components of both Shh and Wnt pathways will have to be established. Second, we will have to determine the role of basal bodies in regulating traffic to and from the cilium. Finally, we will have to analyze the proteomes of individual cilia at various time points in development. This will ultimately provide insight into how cilia may be functioning abnormally during critical stages of development. Further, this type of analysis will be necessary across tissue types. Emerging evidence supports the notion that cilia function differently depending on cell type and on developmental stage (D'Angelo and Franco, 2010
), suggesting a complexity not previously considered but potentially relevant in the context of tissue-specific phenotypes.