Epidermolytic hyperkeratosis (EHK), (bullous congenital ichthyoslform erythroderma), Is an autosomal dominant human skin disorder. Recently, we and others have described mutations in keratins 1 and 10 (K1 and K10) In patients with this disease. Structure-function models predict that these mutations would impair normal filament assembly and function. We have extended our earlier studies to include 8 more Incidences of EHK. In half of these families, we were unable to locate a mutation within the rod domains of either K1 or K10. However, polymorphic restriction site and sequence analysis of the other families revealed a mutational hot spot within the 1A alpha-helical segment of K10. These involve Arginlne to Hlstldlne, Arglnlne to Cystelne and Arglnlne to Leucine substitutions at residue 10 of the rod domain. Interestingly, mutations In the corresponding Arglnine residue in keratin K14 have been Identified In patients with epidermolysis bullosa simplex. The large number of mutations found at this position in both keratins K10 and K14 suggests that other eplthelia cell disorders will be discovered that are caused by the corresponding mutation in related type I keratin genes.
To examine how PRL regulates lymphocyte proliferation, a number of PRL-activated genes were identified from a PRL-dependent rat T lymphoma cell line, Nb2. One of the downstream genes in the PRL signaling cascade was identified as clone 15 (c15). PRL stimulation of quiescent Nb2 T cells results in the expression of a 1.7-kilobase c15 mRNA, which reaches maximum levels between 8 and 10 h after stimulation. Corresponding [3H]thymidine incorporation experiments show that the maximum level of c15 mRNA expression correlates with the G1/S transition phase of the cell cycle. Sequencing of approximately 1.3-kilobase cDNA revealed one open reading frame that predicts a 332-amino acid protein. In vitro transcription/translation of c15 cDNA resulted in the production of a 45-kilodalton protein. Sequence analysis revealed that the c15 open reading frame contains a potential nuclear localization signal, a very acidic region, and a carboxy-terminal region of 94 amino acids which are 68% identical and 78% similar to the nuclear movement protein, NUDC, found in Aspergillus nidulans. Such a high degree of conservation suggests that the NUDC-like motif in c15 has been conserved through evolution for an important structure and/or function.
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