HERITABLE DISORDERS OF CONNECTIVE TISSUE

我们一直在继续我们的研究，以阐明 结缔组织遗传性疾病，特别是成骨 不完美和Ehler-Danlos综合征，并将这一信息应用于 这些疾病的治疗。 我们已经将我们的胶原蛋白分析和RNA杂交方法应用于 (1)两例中重度OI，我们在这两例中都描述了 丝氨酸替代甘氨酸。一个突变位于α-1(I)Gly 352；这是先证者形成的主要α-1(I)链，因为 正常等位基因转录减少。另一种突变是在 α-2(I)Gly 922并导致胶原热稳定性降低 在这种情况下，先证者的未受影响的父亲被证明是一个 突变的嵌合体，并有产生进一步影响的风险 后代。 (2)表达变异、复合杂合子或生殖细胞的病例 用线状嵌合体来探索变异体表达的分子基础 结构蛋白的显性紊乱。 (3)有I型胶原证据的Ehler-Danlos综合征病例 反常现象。我们还发现了一种I型胶原异常。 EDS伴自身免疫性血管炎和胶原特异性的1例 免疫蛋白。 在临床方案中，我们继续我们对生长的研究 OI缺乏，并即将启动一项全面的治疗试验。 用于断奶的协作性交叉支撑方案有 结束了第一阶段，并进行了交接。

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.