The aim of this study is to clarify the implication of ciliary pathway on the onset of the spinal curvature that occurs in Adolescent Idiopathic Scoliosis (AIS) patients through functional studies of two genes: POC5 and TTLL11. Since the genetic implication for AIS is accepted, many association and candidate gene analysis revealed the implication of ciliary genes. The characterisation of these two proteins was assessed by qPCR, WB and immunofluorescence in vitro using control cells and cells derived from AIS patients. The impact of genetic modification of these genes on the functionality of the proteins in vitro and in vivo was analysed in zebrafish model created by CRISPR/Cas9 using microCT and histologic analysis. Our study revealed that mutant cells, for both gene, were less ciliated and the primary cilia was significantly shorter compared to control cells. We also observed a default in cilia glutamylation by immunofluorescence and Western Blot. Moreover, we observed in both zebrafish model, a 3D spine curvature similar to the spinal deformation in AIS. Interestingly, our preliminary results of immunohistology showed a retinal defect, especially at the cone cell layer level. This study strongly supports the implication of the ciliary pathway in the onset of AIS and this is the first time that a mechanism is described for AIS. Indeed, we show that shorter cilia could be less sensitive to environmental factors due to lower glutamylation and result in altered signalling pathway. Identifying the biological mechanism involved is crucial for elucidating AIS pathogenesis.
Marfan syndrome (MFS) is a common connective tissue disorder affecting one in 3300 people worldwide, and is caused by unique mutations in the 65 exon gene for fibrillin-1—an essential microfibril component of ligaments, tendons, and muscle. A recently discovered feature in the Marfan mouse model is increased concentrations of transforming growth factor β, resulting in overgrowth. 70% of patients with MFS have scoliosis of some degree. Can lessons be learned from MFS aetiology and treatment that apply to idiopathic adolescent scoliosis? We aimed to establish whether there is a relationship between the type and location of mutation, and the presence and degree of severity of scoliosis, in patients with MFS. Of 181 consecutive patients with MFS with known causative fibrillin-1 mutations, 93 were male (51%) and 88 female (49%). 28 (15%; ten males, 18 females) of the total group had moderate to severe scoliosis, including two females and two males who had corrective surgery. Of the 16 patients with severe scoliosis (three males, 13 females), Height A rapid adolescent growth spurt to excessive height is a documented clinical feature in MFS. The age of clinical diagnosis as an indication of severity was on average 11·3 years (range 2 days to 36 years), and ten patients were diagnosed before the age of 12 years.Introduction
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