Synteny-defined candidate genes for congenital and idiopathic scoliosis

Abstract

Idiopathic scoliosis (IS) is a common but poorly understood syndrome. Congenital scoliosis (CS) is less common but comparably unexplored. Previous studies suggest that each has a significant genetic component. However, the occurrence of scoliosis in the presence of other hereditary connective tissue syndromes raises the possibility that IS and CS are in fact a heterogeneous group of disorders with varied pathogenetic mechanisms. Mouse mutations have proven informative in identifying genes that are important in the development of the musculoskeletal system and provided important mechanistic insights regarding their roles in human disease. We sought to identify candidate genes for human IS and CS by reviewing mouse mutations with phenotypes affecting the axial skeleton. We performed a systematic review using the Mouse Genome Database (MGD), the Genome Database (GDB), and the Online Mendelian Inheritance in Man (OMIM) world-wide-web sites with additional searches performed based on the results of this initial search. We identified approximately 400 mouse mutations, reviewed approximately 250 of these for vertebral phenotypes, assessed 45 of these for synteny conservation between mouse and man, and identified 28 mouse mutations for which 29 credible candidates for human scoliosis could be identified based on mouse phenotypic and mapping data. For each of these, we have synthesized information about the mouse mutant phenotype, mapping data, information regarding molecular pathogenesis when a specific causative gene has been identified, and information regarding plausible candidates based on map position when the causative gene has not been identified. Among these were three loci for which the mutant gene had been identified and the human homologue was known. Some of the mouse mutants have phenotypes similar to human syndromes.

Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans

“…The pudgy mouse phenotype, which is similarly characterized by severe vertebral and rib defects, 18 has been shown to be due to mutations in DLL3 19,20 . Synteny conversion indicated that the human orthologue for DLL3 localized to 19q13.1 21 . Turnpenny and colleagues subsequently identified mutations in DLL3.…”

Characterization of the Skeletal Fusion with Sterility (<i>sks</i>) Mouse Showing Axial Skeleton Abnormalities Caused by Defects of Embryonic Skeletal Development

“…Therefore, these 20 genes including basic transcription factor 3-like 4 ( Btf3l4 ) and epidermal growth factor receptor pathway substrate 15 ( Eps15 ) are potential candidate genes. Furthermore, the mapping results exclude 2 strong candidate genes, collagen, type IX, alpha 2 ( Col9A2 ) and sex comb on midleg homolog 1 ( Scmh1 ), both located on chromosome 4, distal to the b gene [9, 26]. A mutation in the human homolog of the Col9A2 gene causes multiple epiphyseal dysplasia type 2 [20] resulting in hypoplasia of anterior vertebral elements [2].…”

Congenital and Idiopathic Scoliosis: Clinical and Genetic Aspects

“…We therefore undertook a systematic review of mouse mutations with skeletal, tail, or neuromuscular phenotypes with the goal of identifying potential human candidate genes for CS and IS. 74 When the human homologue of the mouse mutant gene was known, this became a candidate. When such a homologue was not known, the established syntenic relationships between the two species were used to identify additional human candidate genes by their chromosomal locations.…”