Holbrook K A, Byers P H
Departments of Biological Structure, University of Washington School of Medicine, Seattle 98195.
Am J Med Genet. 1989 Sep;34(1):105-21. doi: 10.1002/ajmg.1320340118.
A skin biopsy contains the macromolecules present in most connective tissues: collagens, elastin, glycoproteins, and proteoglycans. The specific combination and assembly of these matrix components and their interactions with other structures (e.g., epidermal appendages, nerve and vascular networks) and cells are responsible for the distinction among specific regions of the dermis. The matrix components are interactive and interdependent and modification of one of them, by extrinsic (environmental) and/or intrinsic (systemic, genetic, age-related) factors, may have consequences on the tissue as a whole. The skin, therefore, provides a window through which it is possible to examine how mutations in one connective tissue macromolecule can change the interactions among matrix components and affect tissue structure and organization. Light and electron microscopic studies of skin from patients with inherited connective tissue disorders (e.g., Ehlers-Danlos syndrome, osteogenesis imperfecta, Marfan syndrome, cutis laxa) have led us to the following generalizations about what components change, how individual collagen or elastic fibers are altered and how individual alterations affect overall dermal organization: 1) There is a limited change in the repertoire of collagen fibrils in the skin; 2) there appears to be a greater range of abnormal structure in dermal elastic fibers than in the collagen fibrils; 3) the morphology of the fibroblastic cells may provide clues to the defect in matrix components; 4) similar structural abnormalities result from different molecular defect; 5) a molecular defect in one connective tissue molecule has consequences for the structural properties of other connective tissue components; and 6) although structural alterations in connective tissue fibers are rarely specific for a given disease, there are characteristic patterns of structural change in the matrix that may be used to confirm a diagnosis. These generalizations show that mutations rarely affect only a single aspect of macromolecular function and because of the interactions of matrix components in this complex organ (skin) often disturb the organization of the entire dermis. Genotype-phenotype relationships are important to understand if effective therapies are to be designed. The structure of skin should provide the next level of integration in our efforts to determine how mutations produce disease.
胶原蛋白、弹性蛋白、糖蛋白和蛋白聚糖。这些基质成分的特定组合与组装，以及它们与其他结构（如表皮附属器、神经和血管网络）和细胞的相互作用，决定了真皮特定区域之间的差异。基质成分相互作用且相互依存，其中任何一种受到外在（环境）和/或内在（全身、遗传、年龄相关）因素的影响而发生改变，都可能对整个组织产生影响。因此，皮肤提供了一个窗口，通过它可以研究一种结缔组织大分子中的突变如何改变基质成分之间的相互作用，并影响组织结构。对遗传性结缔组织疾病（如埃勒斯-当洛综合征、成骨不全、马凡综合征、皮肤松弛症）患者的皮肤进行光镜和电镜研究，使我们得出了以下关于哪些成分发生变化、单个胶原纤维或弹性纤维如何改变以及单个改变如何影响真皮整体结构的一般性结论：1）皮肤中胶原纤维的种类变化有限；2）真皮弹性纤维的异常结构范围似乎比胶原纤维更大；3）成纤维细胞的形态可能为基质成分的缺陷提供线索；4）不同的分子缺陷可导致相似的结构异常；5）一种结缔组织分子中的分子缺陷会对其他结缔组织成分的结构特性产生影响；6）尽管结缔组织纤维的结构改变很少针对某一特定疾病具有特异性，但基质中存在特征性的结构变化模式，可用于确诊。这些一般性结论表明，突变很少只影响大分子功能的一个方面，而且由于这个复杂器官（皮肤）中基质成分的相互作用，常常会扰乱整个真皮的结构。如果要设计有效的治疗方法，了解基因型与表型的关系很重要。皮肤结构应该为我们确定突变如何导致疾病的研究提供下一个整合层面。
