Milewicz D M, Grossfield J, Cao S N, Kielty C, Covitz W, Jewett T
Department of Internal Medicine, University of Texas-Houston Medical School 77030, USA.
J Clin Invest. 1995 May;95(5):2373-8. doi: 10.1172/JCI117930.
Dermal fibroblasts from a 13-yr-old boy with isolated skeletal features of the Marfan syndrome were used to study fibrillin synthesis and processing. Only one half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited into the extracellular matrix. Electron microscopic examination of rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene revealed a heterozygous C to T transition at nucleotide 8176 resulting in the substitution of a tryptophan for an arginine (R2726W), at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals have cardiac or ocular manifestations of the Marfan syndrome. This mutation identifies a putative site for profibrillin to fibrillin processing, and is associated with isolated skeletal features of the Marfan syndrome, indicating that the FBN1 gene is one of the genes that determines height in the general population. The cellular effect of the mutation may be equivalent to a "null" FBN1 allele and may define the phenotype associated with FBN1 "null" alleles.
来自一名患有马凡综合征孤立骨骼特征的13岁男孩的真皮成纤维细胞被用于研究原纤维蛋白的合成和加工。只有一半分泌的原纤维蛋白在细胞外被蛋白水解加工成纤维蛋白并沉积到细胞外基质中。对先证者成纤维细胞制成的旋转阴影微纤维进行电子显微镜检查，结果与对照细胞无法区分。FBN1基因测序显示，在核苷酸8176处有一个杂合的C到T转换，导致在一个紧邻细胞蛋白酶识别的共有序列的位点上，一个色氨酸替代了精氨酸（R2726W）。先证者家族中的其他六个人有与高身材相关的FBN1突变。所有受影响的个体均无马凡综合征的心脏或眼部表现。这种突变确定了一个原纤维蛋白加工成纤维蛋白的假定位点，并与马凡综合征的孤立骨骼特征相关，表明FBN1基因是决定普通人群身高的基因之一。该突变的细胞效应可能等同于一个“无效”的FBN1等位基因，并可能定义与FBN1“无效”等位基因相关的表型。
