Idiopathic Scoliosis Families Highlight Actin-Based and Microtubule-Based Cellular Projections and Extracellular Matrix in Disease Etiology

Abstract

Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family. Across the five families, we identified a total of 270 variants with predicted functional consequences in 246 genes, and found that eight genes were shared by two families. We performed GO term enrichment analyses, with the hypothesis that certain functional annotations or pathways would be enriched in the 246 genes identified in our IS families. Using three complementary programs to complete these analyses, we identified enriched categories that include stereocilia and other actin-based cellular projections, cilia and other microtubule-based cellular projections, and the extracellular matrix (ECM). Our results suggest that there are multiple paths to IS and provide a foundation for future studies of IS pathogenesis.

Exome sequencing analysis identifies frequent oligogenic involvement andFLNBvariants in adolescent idiopathic scoliosis

“…Recently, elongated primary cilia of the osteoblasts of patients with IS were reported 32. Considering the emerging evidence indicating that primary cilia act as mechanosensors in bone structures,33 34 dysregulated ciliogenesis and cilia function-associated cellular-molecular mechanisms might provide another explanation for the IS aetiology 35. In our study, we demonstrate that some ciliary genes might contribute to AIS with oligogenic inheritance.…”

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

“…Although dynein family genes related to axonemal structure organization and motility were reported to be associated with AIS before (Baschal et al, 2018), the variants of four out of the above five genes identified in our WES study of Southern Chinese patients are novel. These variants are located on DNALI1 and DNAH1 genes from axonemal dynein family, and DNAAF1 and ZMYND10 genes from axonemal dynein assembly factors.…”

“…Genomic sequencing approaches have identified mutations in familial AIS pedigrees, including mutations in HSPG2, POC5, AKAP2, MAPK7, and CELSR2 genes (Baschal et al, 2014;Patten et al, 2015;Li et al, 2016;Einarsdottir et al, 2017;Gao et al, 2017). WES in AIS cohort indicated that rare variants in FBN1/2, musculoskeletal collagen genes, including 14 collagen genes, and cilia-associated genes, were enriched in AIS patients (Buchan et al, 2014;Haller et al, 2016;Baschal et al, 2018). Together, these efforts suggest a complex polygenic disease model for AIS, encompassing a range of genetic and phenotypic heterogeneity.…”

Rare coding variants in axonemal dynein heavy chain genes are associated with adolescent idiopathic scoliosis

“…We identi ed a signi cant association of variants in axonemal dynein heavy chain genes in AIS patients compared to controls. An exome sequencing study in multigenerational families with idiopathic scoliosis also implicated components of the microtubule cytoskeleton including DNAH6 and DNAH8 (Baschal, Terhune et al 2018). We generated a stable dnah10 ut28/ut28 mutant zebra sh line, which models aspects of AIS including late-onset, atypical three-dimensional spine curvatures without patterning defects.…”