PATHOBIOLOGY OF INBORN SKELETAL DISEASES

胶原蛋白的潜在结构缺陷正在人类中寻找 结缔组织疾病 特别令人感兴趣的是那些天生的 影响肌肉骨骼的疾病，更常见的是 Ehlers-Danlos综合征、成骨不全和马凡氏综合征。 一 这种稀有组织的丰富来源，我们可以在这里和通过 合作联系。 我们的主要方法是直接分析组织 基质胶原蛋白。 花费了一部分努力 筛查有希望的新病例，但主要精力用于随访 对已鉴定的胶原蛋白突变体进行深入研究。 虽然胶原蛋白紊乱 是主要目标，蛋白聚糖缺陷的迹象将被追踪。 一 主要目标是获得对结构之间关系的独特见解 和胶原蛋白的功能，以及帮助检测，治疗和预防 这些骨骼疾病 胶原蛋白交联备受关注 由于交联缺陷对于许多已知的疾病是常见的， 胶原蛋白分子，似乎是结构完整性的良好指标。 技术包括平板凝胶电泳和反相HPLC 胶原多肽和衍生片段的层析，和 受影响组织中胶原纤维和细胞的电子显微镜检查。 在适当的情况下，将培养皮肤成纤维细胞以表征 原胶原蛋白产品。 将冷冻适当的组织标本， 合作者未来的DNA和RNA分析应指出缺陷， 蛋白质水平。 过去两年按组织分类的具体随访病例 筛查包括：1）一个新的EDS VII病例，其中一个短缺失 指示跨越α 2（I）-链氨基端肽结构域的氨基酸序列; 2）a 皮肤中无羟赖氨酸和赖氨酰吡啶啉的EDS VI新病例 替代软骨中的羟基赖氨酰吡啶啉交联; 3）两种致命的 新生儿脊椎骨骺发育不良病例，其中一个结构突变 4）软骨发育不全II型（Langer-Saldino）， 软骨中完全缺乏II型胶原; 5）来自几个病例的骨 成骨细胞 此外，我们将筛选交联 马凡氏病患者的主动脉胶原异常。 损害骨骼结构和发育的先天性疾病 占1200万美国人的很大一部分， 出生缺陷 胶原蛋白异常会导致 这些数字。

Underlying structural defects of collagen are being sought in human connective tissues diseases. Of particular interest are those inborn disorders that affect the musculoskeleton, the more common ones being the Ehlers-Danlos syndromes, osteogenesis imperfecta, and Marfan's syndrome. A rich source of such rare tissues is available to us here and through collaborative contacts. Our primary approach is direct analysis of tissue matrix collagens by biochemical techniques. A portion of effort is spent screening promising new cases, but the main effort is devoted to follow-up studies in depth on identified collagen mutants. Though collagen disorders are the prime target, signs of proteoglycan defects would be pursued. A major goal is to gain unique insights on the relationship between structure and function of collagen, as well as helping detect, treat and prevent these skeletal disorders. Collagen cross-linking receives keen attention since cross-linking defects are common to many of the known diseases of the collagen molecule, and seems a good index of structural integrity. Techniques include slabgel electrophoresis and reverse phase HPLC chromatography of collagen polypeptides and derived fragments, and electronmicroscopy of collagen fibrils and cells in affected tissues. Where appropriate skin fibroblasts will be grown to characterize procollagen products. Appropriate tissue specimens will be frozen for future DNA and RNA analyses by collaborators should defects be indicated at the protein level. Specific cases for follow-up identified in the last two years by tissue screening include: 1) a new case of EDS VII in which a short deletion spanning the Alpha2(I)-chain amino-telopeptide domain is indicated; 2) a new case of EDS VI with no hydroxylysine in skin and lysyl pyridinoline replacing hydroxylysyl pyridinoline cross-links in cartilage; 3) two lethal newborn cases of spondylepiphyseal dysplasia in which a structural mutation of Alpha1(II) is present; 4) achondrogenesis type II (Langer-Saldino) that totally lacks type II collagen in cartilage; and 5) bone from several cases of osteogenesis imperfecta. In addition we will screen for cross-linking abnormalities in aortic collagen of Marfan's patients. Inborn disorders that impair the structure and development of the skeleton account for a significant fraction of the 12 million Americans who have birth defects. Collagen abnormalities will account for a significant number of these.