Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

Abstract

Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

The value of genome-wide analysis in craniosynostosis

“…Also, we observed enrichment of heterozygous carriers of variants in CS-related autosomal recessive genes from the ciliopathy spectrum (e.g., IFT122, IFT140, and WDR19 -Supplementary Table S4). These findings, together with results from previous studies showing enrichment of damaging variants in genes associated with SCS in patients with NCS, suggest an oligogenic involvement with incomplete penetrance in the occurrence of single-suture NCS (Clarke et al, 2018;Gustafson et al, 2019;Tiberio et al, 2021).…”

An additional whole-exome sequencing study in 102 panel-undiagnosed patients: A retrospective study in a Chinese craniosynostosis cohort

“…We found two sagittal patients, case W015 and W038, carried heterozygous missense variants in EVC. To date, only a single case of sagittal synostosis has been reported in a patient affected by Ellis-van Creveld syndrome, but this disorder is usually caused by homozygous variants in either the EVC or EVC2 genes (Fischer et al, 2015;Tiberio et al, 2021). Although there was no other candidate variants and inheritance validation composing compound heterozygotes in this study, the candidate variants suggest attention on EVC.…”

“…The recurrence of the same candidate gene in different patients also increased its potential of pathogenicity. Among all pathophysiology of CRS, the genes orchestrating the primary cilium structure and function were also known to play an important role (Tiberio et al, 2021). The EVC encodes a positive regulator downstream the HH signaling, expressed on the ciliary membrane as a single-pass transmembrane protein.…”

“…Furtherly, SOST and AMER1 were causal for cranial sclerosis with craniofacial abnormalities. DNAH11 encodes critical protein for cilia, which might impact development of cranial sutures the primary cilium structure and function (Tiberio et al, 2021).…”