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Congenital and Idiopathic Scoliosis: Clinical and Genetic Aspects

Medical Genetics Services, Marshfield Clinic, Marshfield, Wisconsin

Robert D. Blank, MD, PhD

Section of Endocrinology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin

Cathleen L. Raggio, MD

Department of Pediatric Orthopedics, Hospital for Special Surgery, New York, New York

Sajid Merchant, MS, BSc

Medical Genetics Services, Marshfield Clinic, Marshfield, Wisconsin

F. Stig Jacobsen, MD

Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, Wisconsin

Thomas Faciszewski, MD

Department of Orthopedic Spine Surgery, Marshfield Clinic, Marshfield, Wisconsin

Sanjay K. Shukla, PhD

Clinical Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin

Anne R. Greenlee, PhD

Reproductive Toxicology, Marshfield Clinic Research Foundation, Marshfield, Wisconsin

Cory Reynolds, MS, BS

Clinical Research Center, Marshfield Clinic Research Foundation, Marshfield, Wisconsin

David B. Schowalter, MD, PhD

Medical Genetics, Mayo Clinic, Rochester, Minnesota

REPRINT REQUESTS: Philip F. Giampietro, MD, PhD, Medical Genetics Services, Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI 54449, Telephone: 715-389-4456, Fax: 715-389-4399, Email: giampietro.philip{at}marshfieldclinic.org

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.

Key Words: Congenital scoliosis • Synteny • Idiopathic scoliosis • Spinal development • Developmental genes