Developmental Mechanisms of Human Idiopathic Scoliosis

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Project Summary/Abstract Adolescent idiopathic scoliosis (AIS) is a twisting condition of the spine and is the most common pediatric musculoskeletal disorder, affecting 3% of children worldwide. Children with AIS risk severe disfigurement, back pain, and pulmonary dysfunction later in life. Girls requiring treatment for AIS outnumber boys by more than five-fold, for reasons that are unknown. AIS is treated symptomatically rather than preventively because the underlying etiology is unknown. Hospital charges for AIS surpass one billion dollars annually in the U.S. and are rising significantly faster than for other pediatric procedures. Our overall purpose is to understand the biologic causes of AIS as a means to early diagnosis, prevention and non-invasive biologic treatment. Adolescent idiopathic scoliosis is a complex genetic disease. Genome wide association studies (GWAS) of common non-coding variants by our group and others have identified AIS-associated haplotypes, but the mechanistic basis of these associations remains to be defined. Furthermore these findings explain less than 5% of overall heritability due in part to the fact that the AIS exome has yet to be fully interrogated. Another barrier to understanding the pathogenesis of AIS in humans has been the lack of appropriate, genetically- defined animal models that are essential for defining spatiotemporal involvement in the disease. Finally the developmental regulation of postnatal spinal development generally, and the specific tissue of origin in AIS specifically, are poorly understood. To address these issues we have established an innovative collaborative approach combining unbiased gene discovery in humans, modeling and gene discovery in zebrafish, and genomic analysis of postnatal spine development. Specifically, the component activities of our proposed Program will synergize to yield the tools and fundamental knowledge that the field of AIS research has lacked, addressing the following goals: (1) We will define the genetic architecture conveying AIS susceptibility as identified in human populations; (2) We will develop the first genetically tractable vertebrate system for modeling AIS and studying the functional consequences of AIS mutations identified in humans; (3) We will define cis-and trans-regulation of AIS causal genes; (4) We will pilot a large-scale genomics platform to begin to characterize the molecular mechanisms controlling spinal development; (5) We will identify and characterize causal mutations in patients that may identify gene-based AIS subtypes; (6) By filling gaps in fundamental knowledge of the disease we will drive innovative efforts to develop new therapies for AIS. Our discoveries will spur the field toward much-needed hypothesis-driven research aimed at early molecular diagnosis, prevention and therapies. We also expect that these studies will enlighten other structural defects of humans.