Congenital and idiopathic scoliosis: clinical and genetic aspects

Abstract

Objective: Genetic and environmental factors influencing spinal development in lower vertebrates are likely to play a role in the abnormalities associated with human congenital scoliosis (CS) and idiopathic scoliosis (IS). An overview of the molecular embryology of spinal development and the clinical and genetic aspects of CS and IS are presented. Utilizing synteny analysis of the mouse and human genetic databases, likely candidate genes for human CS and IS were identified.

Design: Review and synteny analysis.

Methods: A search of the Mouse Genome Database was performed for "genes," "markers" and "phenotypes" in the categories Neurological and neuromuscular, Skeleton, and Tail and other appendages. The Online Mendelian Inheritance in Man was used to determine whether each mouse locus had a known human homologue. If so, the human homologue was assigned candidate gene status. Linkage maps of the chromosomes carrying loci with possibly relevant phenotypes, but without known human homologues, were examined and regions of documented synteny between the mouse and human genomes were identified.

Results: Searching the Mouse Genome Database by phenotypic category yielded 100 mutants of which 66 had been mapped. The descriptions of each of these 66 loci were retrieved to determine which among these included phenotypes of scoliosis, kinky or bent tails, other vertebral abnormalities, or disturbances of axial skeletal development. Forty-five loci of interest remained, and for 27 of these the comparative linkage maps of mouse and human were used to identify human syntenic regions to which plausible candidate genes had been mapped.

Conclusion: Synteny analysis of mouse candidate genes for CS and IS holds promise due to the close evolutionary relationship between mice and human beings. With the identification of additional genes in animal model systems that contribute to different stages of spine development, the list of candidate genes for CS and IS will continue to grow.

Figure 1

Commonly encountered vertebral malformations associated with CS including an unsegmented bar (A), single hemivertebrae (B) and multiple hemivertebrae (C).

Figure 2

Radiograph illustrating multiple segmentation abnormalities of the thoracic spine.

Figure 3

A schematic diagram of murine embryologic development of somite, sclerotome and vertebral body with some of the murine genes involved at different stages. Segmentation is mediated by a molecular segmentation clock operating through the Notch signaling pathway. Segmental boundary formation is mediated by decreased concentrations of fibroblast growth factor 8. Pax1 and Mox1 are involved in sclerotome condensation and subdivision into anterior and posterior halves. Transverse embryo sections and corresponding frontal embryo sections are shown. Other genes such as Gli2, Unex4.1, BMP-7 and Jun are involved in vertebrae differentiation and ossification.