Figure - available from: Frontiers in Cell and Developmental Biology
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C2cd3ex2/ex2 mutants present with phenotypes indicative of a ciliopathy. (A) Schematic of CRISPR-targeted 8 bp deletion in C2cd3 at exon 2 which results in a premature stop codon. (B,C) Lateral and (B′,C′) frontal views of E9.5 wild-type and C2cd3ex2/ex2 embryos. C2cd3ex2/ex2 embryos exhibit pericardial edema (white dashed line), tight mesencephalic flexure (black line), mandibular hypoplasia (white arrowhead), abnormal heart looping (black arrow), and exencephaly (black asterisk). The heart is labeled with red asterisks. (B′′,C′′) Axonemal (Arl13b) and basal body (gamma-tubulin) immunostaining of E9.5 embryos in wild-type and C2cd3ex2/ex2 embryos. Scale bars for panels (B–C′): 0.5 mm; (B′′–C′′): 50 μm. (D) Western blot of E9.5 wild-type and C2cd3ex2/ex2 whole embryos showing deletion of the 255 kDa isoform in both C57BL/6J and CD1 backgrounds. The ratio of Gli3FL/Gli3R is increased in C2cd3ex2/ex2 compared to wild-type.
Source publication
The primary cilium is a ubiquitous, microtubule-based cellular organelle. Primary cilia dysfunction results in a group of disorders termed ciliopathies. C2 domain containing 3 centriole elongation regulator (C2cd3), encodes a centriolar protein essential for ciliogenesis. Mutations in human C2CD3 are associated with the human ciliopathy Oral-Facial...
Citations
... Like C2CD3, the OFD1 protein is also involved in primary cilia biogenesis [46,47]. The OFD1 protein contains a Lis homology (LisH) domain in its N-terminal region and several coiled-coil (CC) domains located C-terminal to the LisH motif. ...
Background
Syndromic ciliopathies are a group of congenital disorders characterized by broad clinical and genetic overlap, including obesity, visual problems, skeletal anomalies, mental retardation, and renal diseases. The hallmark of the pathophysiology among these disorders is defective ciliary functions or formation. Many different genes have been implicated in the pathogenesis of these diseases, but some patients still remain unclear about their genotypes.
Methods
The aim of this study was to identify the genetic causes in patients with syndromic ciliopathy. Patients suspected of or meeting clinical diagnostic criteria for any type of syndromic ciliopathy were recruited at a single diagnostic medical center in Southern Taiwan. Whole exome sequencing (WES) was employed to identify their genotypes and elucidate the mutation spectrum in Taiwanese patients with syndromic ciliopathy. Clinical information was collected at the time of patient enrollment.
Results
A total of 14 cases were molecularly diagnosed with syndromic ciliopathy. Among these cases, 10 had Bardet-Biedl syndrome (BBS), comprising eight BBS2 patients and two BBS7 patients. Additionally, two cases were diagnosed with Alström syndrome, one with Oral-facial-digital syndrome type 14, and another with Joubert syndrome type 10. A total of 4 novel variants were identified. A recurrent splice site mutation, BBS2: c.534 + 1G > T, was present in all eight BBS2 patients, suggesting a founder effect. One BBS2 patient with homozygous c.534 + 1G > T mutations carried a third ciliopathic allele, TTC21B: c.264_267dupTAGA, a nonsense mutation resulting in a premature stop codon and protein truncation.
Conclusions
Whole exome sequencing (WES) assists in identifying molecular pathogenic variants in ciliopathic patients, as well as the genetic hotspot mutations in specific populations. It should be considered as the first-line genetic testing for heterogeneous disorders characterized by the involvement of multiple genes and diverse clinical manifestations.
... Third, the AP2-Cre 368 driver recombined in the surface and oral ectoderm, the CNCC-derived mesenchyme, and the 369 neuroectoderm (Macatee et al., 2003). To determine the tissue-specific requirement for C2cd3 function, we 370 utilized previously generated mice with a C2cd3 ex4-5flox allele (Chang et al., 2021) in combination with these 371 ...
The mandible is composed of several musculoskeletal tissues including bone, cartilage, and tendon that require precise patterning to ensure structural and functional integrity. Interestingly, most of these tissues are derived from one multipotent cell population called cranial neural crest cells (CNCCs). How CNCCs are properly instructed to differentiate into various tissue types remains nebulous. To better understand the mechanisms necessary for the patterning of mandibular musculoskeletal tissues we utilized the avian mutant talpid2 (ta2) which presents with several malformations of the facial skeleton including dysplastic tendons, mispatterned musculature, and bilateral ectopic cartilaginous processes extending off Meckel’s cartilage. We found an ectopic epithelial BMP signaling domain in the ta2 mandibular prominence (MNP) that correlated with the subsequent expansion of SOX9+ cartilage precursors. These findings were validated with conditional murine models suggesting an evolutionarily conserved mechanism for CNCC-derived musculoskeletal patterning. Collectively, these data support a model in which cilia are required to define epithelial signal centers essential for proper musculoskeletal patterning of CNCC-derived mesenchyme.
