Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity with a prevalence of 1%-3%. Genetic factors have been associated with the etiology of AIS. However, previous studies mainly focused on common single nucleotide polymorphisms which confer modest disease risk. Recently, rare variants in FBN1 and other extracellular matrix genes have been implicated in AIS, suggesting a potential overlapping disease etiology between AIS and hereditary connective tissue disorders (HCTD). In this study, we systematically analyzed rare variants in a set of HCTD-related genes in 302 AIS patients who underwent exome sequencing. We firstly focused on pathogenic variants based on a monogenic inheritance and identified nine disease-associated variants in FBN1, COL11A1, COL11A2 and TGFBR2. We then explored the potential interactions between variants in different genes based on the case-control statistics. We identified three ADAMTSL2-LTBP4 variant pairs in three AIS patients and none in controls. Furthermore, we revealed that the variant pairs identified in these genes could affect the interaction between ADAMTSL2 and LTBP4 and upregulate TGF-β signaling pathway in human fibroblasts. Our findings implicate that the aberrant interaction between mutated ADAMTSL2 and LTBP4 was associated with AIS.
Keywords: ADAMTS-like protein 2 (ADAMTSL2); Adolescent idiopathic scoliosis; Hereditary connective tissue disorders; Latent transforming growth factor-beta-binding protein 4 (LTBP4); TGF-β signaling pathway.
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