Christine Gurnett, M.D., Ph.D.
Gene Discovery in Adolescent Idiopathic Scoliosis
Abstract
Adolescent idiopathic scoliosis is a disorder of unknown etiology that predominately affects females. Scoliosis is defined as a lateral curvature of the spine measuring greater than 10 degrees on posteroanterior spine radiographs. The incidence of scoliosis is much higher in females, particularly for curves greater than 30 degrees with a female-to-male ratio approaching 10:1. Thus, females are disproportionately affected by the physical and social effect of scoliosis, and undergo the majority of the 15-20,000 spinal fusions performed per year for severe scoliosis. A genetic predisposition to scoliosis is evidenced by the high rates of concordance in twin studies and the increased risk to first-degree relatives. However, the gene responsible for adolescent idiopathic scoliosis is unknown. The goal of this research is to define the gene(s) responsible for this disorder through linkage analysis of a large Caucasian family in which idiopathic scoliosis and pectus excavatum segregates in an autosomal dominant manner. This family consists of twelve females with idiopathic scoliosis, including a proband that was treated with spinal fusion surgery, as well as three males with pectus excavatum. Linkage analysis will be performed using DNA from affected and unaffected individuals from this family in order to identify chromosomal regions segregating with disease. The second aim of this study is to fine map regions of linkage and to identify disease-causing mutations in this family. Identification of genes causing scoliosis may allow at risk individuals to be identified prior to the onset of curvature and to be stratified earlier into therapeutic protocols for curve prevention.
Hypothesis
Adolescent idiopathic scoliosis results from a single gene mutation in a large family in which scoliosis and pectus excavatum segregate
Specific Aims
- Map the chromosomal loci responsible for autosomal dominant idiopathic scoliosis in a single large family (SC-6061)
Parametric linkage analysis will be performed on a large family with 12 females affected with scoliosis and 3 males with pectus excavatum using Affymetrix GeneMapping 10K SNP data. - Fine map regions of linkage and sequencing of candidate genes within linkage intervals
Microsatellite markers within the chromosomal loci identified in aim 1 will be typed in all members of family SC01 in order to define boundaries of linkage region. Candidate genes within these areas will be resequenced to determine disease-causing mutation.
