We have continued our studies to elucidate the molecular mechanisms of heritable disorders of connective tissue, specifically osteogenesis imperfecta and Ehlers-Danlos syndrome, and to apply this information to the treatment of these disorders. We have applied our collagen protein analysis and RNA hybrid methodology to (1) two moderately severe cases of OI, in both of which we delineated substitutions of serine for glycine. One mutation is at alpha-1(I) gly 352; This is the predominant alpha-1(I) chain made by the proband because the normal allele has reduced transcription. The other mutation is at alpha-2(I) gly 922 and causes reduced thermal stability of the collagen helix; in this case, the proband's unaffected father was shown to be a mosaic for the mutation and at risk of producing further affected offspring. (2) Cases with variability of expression, compound heterozygosity or germ line mosaicism to explore the molecular basis of variable expression in a dominant disorder of structural protein. (3) Cases of Ehlers-Danlos syndrome with evidence of a type I collagen abnormality. We have also demonstrated a type I collagen abnormality in a case of EDS with autoimmune vasculitis and a collagen-specific immunoprotein. In clinical protocols, we have continued our investigation of growth deficiency in OI and are about to initiate a full-scale treatment trial. The collaborative cross-over bracing protocol for weaning of braces has concluded Phase 1 and crossed-over.
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