Kimonis V, DiGiovanna J J, Yang J M, Doyle S Z, Bale S J, Compton J G
Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Invest Dermatol. 1994 Dec;103(6):764-9. doi: 10.1111/1523-1747.ep12412771.
Mutations in keratin 9 have been found in families with an epidermolytic form of palmar-plantar keratoderma (PPK). In another form of PPK (Unna-Thost type), epidermolysis is not observed histologically. We studied a pedigree with this non-epidermolytic form of PPK. By gene linkage analysis, the type I keratin locus could be excluded but complete linkage with the type II keratin region was found. Sequence analysis identified a single base change in the amino-terminal V1 variable subdomain of keratin 1, which caused a lysine to isoleucine substitution. This non-conservative mutation completely cosegregated with the disease and was not observed in 50 unrelated unaffected individuals. An examination of keratin amino-terminal sequences revealed a previously unreported 22-residue window in the V1 subdomain that is conserved among most type II keratins. The altered lysine is an invariant residue in this conserved sequence. Previously described keratin mutations affect the central regions important for filament assembly and stability, and cause diseases characterized by cellular degeneration or disruption. This is the first disease mutation in a keratin chain variable end region. The observation that it is not associated with epidermolysis supports the concept that the amino-terminal domain of keratins may be involved in supramolecular interactions of keratin filaments rather than stability. Therefore, hyperkeratosis associated with this mutation may be due to perturbations in the interactions of the keratin end domain with other cellular components.
在患有掌跖角化病（PPK）表皮松解型的家族中发现了角蛋白9的突变。在另一种PPK形式（Unna-Thost型）中，组织学上未观察到表皮松解。我们研究了一个患有这种非表皮松解型PPK的家系。通过基因连锁分析，可以排除I型角蛋白基因座，但发现与II型角蛋白区域完全连锁。序列分析确定角蛋白1氨基末端V1可变亚结构域中有一个单碱基变化，导致赖氨酸被异亮氨酸取代。这种非保守突变与疾病完全共分离，在50名无关的未受影响个体中未观察到。对角蛋白氨基末端序列的检查揭示了V1亚结构域中一个以前未报道的22个残基的窗口，该窗口在大多数II型角蛋白中是保守的。改变的赖氨酸是这个保守序列中的一个不变残基。先前描述的角蛋白突变影响对细丝组装和稳定性很重要的中央区域，并导致以细胞变性或破坏为特征的疾病。这是角蛋白链可变末端区域的第一个疾病突变。它与表皮松解无关的观察结果支持了这样的概念，即角蛋白的氨基末端结构域可能参与角蛋白细丝的超分子相互作用而不是稳定性。因此，与该突变相关的角化过度可能是由于角蛋白末端结构域与其他细胞成分相互作用的扰动。
