Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate

Abstract

Ciliopathies are pleiotropic human diseases resulting from defects of the primary cilium, and these patients often have cleft lip and palate. IFT88 is required for the assembly and function of the primary cilia, which mediate the activity of key developmental signaling pathways. Through whole exome sequencing of a family of three affected siblings with isolated cleft lip and palate, we discovered that they share a novel missense mutation in IFT88 (c.915G > C, p.E305D), suggesting this gene should be considered a candidate for isolated orofacial clefting. In order to evaluate the function of IFT88 in regulating craniofacial development, we generated Wnt1-Cre;Ift88fl/fl mice to eliminate Ift88 specifically in cranial neural crest (CNC) cells. Wnt1-Cre;Ift88fl/flpups died at birth due to severe craniofacial defects including bilateral cleft lip and palate and tongue agenesis, following the loss of the primary cilia in the CNC-derived palatal mesenchyme. Loss of Ift88 also resulted in a decrease in neural crest cell proliferation during early stages of palatogenesis as well as a downregulation of the Shh signaling pathway in the palatal mesenchyme. Importantly, Osr2KI-Cre;Ift88fl/flmice, in which Ift88 is lost specifically in the palatal mesenchyme, exhibit isolated cleft palate. Taken together, our results demonstrate that IFT88 has a highly conserved function within the primary cilia of the CNC-derived mesenchyme in the lip and palate region in mice and is a strong candidate as an orofacial clefting gene in humans.

A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness

“…This non‐motile structure acts as a cell signaling center, contributing to normal development through the regulation of major signaling pathways, for example, Hedgehog and PDGF (reviewed in Goetz & Anderson, ). Genetic defects in primary cilia formation, maintenance, or function underlie a wide array of ciliopathies in human including craniofacial, brain and heart malformations, and retinal and hearing defects (Guemez‐Gamboa, Coufal, & Gleeson, ; May‐Simera & Kelley, ; Tian et al, ; Willaredt, Gorgas, Gardner, & Tucker, ; Yildiz & Khanna, ).…”

A novel PTCH1 mutation underlies nonsyndromic cleft lip and/or palate in a Han Chinese family

“…Moreover, GWAS identifies only the association between the risk locus and the disease, rather than the actual causal relationship, making it difficult to interpret the underlying mechanisms of phenotype occurrence. In recent years, next‐generation sequencing, including whole‐genome and WES, has been used to determine causal variation and interpret the aetiologic mechanisms of the NSCL/P hereditary pedigree (Tian et al., ; Wu et al., ). These techniques complement GWASs and together cover the spectrum of NSCL/P mutations.…”

“…Therefore, it is difficult to determine the association between NSCL/P and those rare variants with lower allele frequencies (Vieira, 2008 (Tian et al, 2017;Wu et al, 2015). These techniques complement GWASs and together cover the spectrum of NSCL/P mutations.…”

“…As a genetically complex disease, NSCL/P may have multiple genetic models, including dominant (Birnbaum et al, 2008;Holzinger et al, 2017;Tian et al, 2017) and recessive inheritance (Marazita et al, 2004;Moura, Cirio, & Pimpao, 2012). Based on the family pedigree information in this study, an autosomal dominant Mendelian inheritance model was considered the best fit, although we cannot eliminate the possibility of de novo, homozygous, or compound heterozygous models.…”

Contribution of cranial neural crest cells to mouse skull development

“…Deletion of IFT20 in neural crest cells leads to skeletal dysplasia, such as osteopenia in the facial region (Noda et al, 2016). Deletion of IFT88 results in a decrease in neural crest cell proliferation at early stages (Tian et al, 2017). Polycystin 2 (Pkd2) localized in primary cilia, and conditional deletion of Pkd2 in neural crest-derived cells causes malformed skull shapes (Khonsari et al, 2013).…”