Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive osteochondrodysplasia characterized by malformation of the vertebrae and distortions of the epiphyses within major joints. Short stature and osteoarthritis are the principal problems suffered by affected men. SEDT has been mapped to Xp22, but the SEDT gene defect is unknown. Characterization of the clinical and radiographic evolution of SEDT in a large six-generation kindred from Arkansas has documented a postnatal defect of skeletal development. Affected hemizygous males have radiographically normal vertebrae at birth, but soon after manifest aberrant endochondral bone formation reflected by an inapparent ring apophysis in vertebrae and mishappen epiphyses. Degeneration of intervertebral discs leads to loss of height and destruction of spinal facet joints, and femoral head and neck deformity cause degenerative disease of the hips. Obligate carrier women in this kindred, heterozygous for the SEDT gene defect, demonstrate subtle abnormalities. The cumulative radiographic findings suggest a disturbance in a gene that conditions endochondral bone formation primarily in the axial skeleton. The SEDT gene will be identified.
Specific aims first confirm and narrow the candidate region in Xp22.2 using linkage analysis for this six-generation kindred, then isolate and characterize candidate genes, and identify which gene is responsible for SEDT. Candidate genes will be isolated using a positional cloning approach, a modified candidate gene approach, and a genomic sequence driven approach. The SEDT gene will be identified and confirmed by mutational analysis of affected individuals. Characterization of the SEDT gene will establish the etiology for this skeletal disorder, reveal a new and important factor in endochondral bone formation, and provide significant insight concerning cartilage biology.
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