GENETIC MUTATIONS IN THE K1 AND K10 GENES OF PATIENTS WITH EPIDERMOLYTIC HYPERKERATOSIS - CORRELATION BETWEEN LOCATION AND DISEASE SEVERITY
GENETIC MUTATIONS IN THE K1 AND K10 GENES OF PATIENTS WITH EPIDERMOLYTIC HYPERKERATOSIS - CORRELATION BETWEEN LOCATION AND DISEASE SEVERITY
复制标题
DOI：
10.1172/jci117132
复制
发表时间：
1994-04-01
影响因子：
15.9
通讯作者：
FUCHS, E
中科院分区：
文献类型：
--
作者：
SYDER, AJ;YU, QC;FUCHS, E
表皮角化过度（EH）是一种由表皮分化特异性角蛋白K1和K10基因突变引起的皮肤病。为了探索突变的异质性，并评估疾病严重程度和突变干扰角蛋白网络形成的程度之间是否存在相关性，我们确定了4例重度EH和1例异常轻度病例的遗传基础。两个严重的情况下，有相同的突变，K10-R156：C，在保守的精氨酸，我们以前显示突变为组氨酸在两个无关的EH家族。另一个严重的病例在6个残基外有一个突变，仍然在K10的α-螺旋杆结构域的氨基末端。另一个严重的病例在K1杆的保守羧基端有突变。相比之下，受影响的成员的轻度家族有一个突变的保守的羧基端的K10杆。通过基因工程和基因转染，我们证明了每个突变在功能上负责角蛋白丝畸变，这是典型的角化细胞培养从这些患者。此外，我们表明，轻度EH突变严重影响细丝网络的形成。总之，我们的研究加强了纤维扰动，细胞脆弱性和退化之间的联系。
Epidermolytic hyperkeratosis (EH) is a skin disease caused by mutations in the genes encoding K1 and K10, the differentiation-specific keratins of epidermis. To explore the heterogeneity of mutations and to assess whether a correlation exists between disease severity and the extent to which a mutation interferes with keratin network formation, we determined the genetic bases of four severe incidences of EH and one unusually mild case. Two severe cases have the same mutation, K10-R156:C, at a conserved arginine that we previously showed was mutated to a histidine in two unrelated EH families. An additional severe case has a mutation six residues away, still within the amino end of the alpha-helical rod domain of K10. The other severe case has a mutation in the conserved carboxy end of the K1 rod. In contrast, affected members of the atypically mild family have a mutation just proximal to the conserved carboxy end of the K10 rod. By genetic engineering and gene transfection, we demonstrate that each mutation is functionally responsible for the keratin filament aberrations that are typical of keratinocytes cultured from these patients. Moreover, we show that the mild EH mutation less severely affects filament network formation. Taken together, our studies strengthen the link between filament perturbations, cell fragility, and degeneration.