TY - JOUR
T1 - The genetic basis of epidermolytic hyperkeratosis
T2 - A disorder of differentiation-specific epidermal keratin genes
AU - Cheng, Jian
AU - Syder, Andrew J.
AU - Yu, Qian Chun
AU - Letal, Anthony
AU - Paller, Amy S.
AU - Fuchs, Elaine
N1 - Funding Information:
We thank Dr. Roger Pearson (Rush Medical School, Chicago, Illinois), Dr. Ruth Freinkel (Northwestern Medical School, Chicago, Illinois), and Dr.VirginiaSybertand Dr. BeverlyDale(Universityof Washington, Seattle) for providing us with EH skin biopsies that did not have the Arg-I 58+His mutation. We especially thank the Foundation for lchthy osis and Related Skin Types (FIRST) and the EH families, who so willingly participated in these studies. We thank Dr. Graham Bell (University of Chicago) for providing us with genomic DNA samples from normal individuals. We thank Grazina Traska for her technical assistance in cell culture and Dr. Pierre Coulombe (Department of Biological Chemistry, Johns Hopkins University Medical School, Baltimore, Maryland) for his helpful comments and for providing the immu-noelectron micrographs of normal human skin. This work was supported by grants from the Howard Hughes Medical Institute and from the National Institutes of Health (AR27883).
PY - 1992/9/4
Y1 - 1992/9/4
N2 - Epidermolytic hyperkeratosis (EH) is a skin disease characterized by keratin filament clumping and degeneration in terminally differentiating epidermal cells. We have discovered that the genetic basis for EH resides in mutations in differentiation-specific keratins. Two of six distinct incidences of EH had a keratin 10 (K10) point mutation in a highly conserved arginine. Remarkably, this same residue is mutated in the basal epidermal K14 in three incidences of another skin disease, epidermolysis bullosa simplex (EBS). By genetic engineering, gene transfection, and 10 nm filament assembly, we show that this mutation is functionally responsible for the keratin filament clumping that occurs in basal (EBS) or suprabasal (EH) cells. These studies strengthen the link between filament perturbations, cell fragility, and degeneration first established with EBS. They also suggest a correlation between filament disorganization and either cytokinesis or nuclear shape, giving rise to the seemingly binuceate cells typical of EH.
AB - Epidermolytic hyperkeratosis (EH) is a skin disease characterized by keratin filament clumping and degeneration in terminally differentiating epidermal cells. We have discovered that the genetic basis for EH resides in mutations in differentiation-specific keratins. Two of six distinct incidences of EH had a keratin 10 (K10) point mutation in a highly conserved arginine. Remarkably, this same residue is mutated in the basal epidermal K14 in three incidences of another skin disease, epidermolysis bullosa simplex (EBS). By genetic engineering, gene transfection, and 10 nm filament assembly, we show that this mutation is functionally responsible for the keratin filament clumping that occurs in basal (EBS) or suprabasal (EH) cells. These studies strengthen the link between filament perturbations, cell fragility, and degeneration first established with EBS. They also suggest a correlation between filament disorganization and either cytokinesis or nuclear shape, giving rise to the seemingly binuceate cells typical of EH.
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U2 - 10.1016/0092-8674(92)90314-3
DO - 10.1016/0092-8674(92)90314-3
M3 - Article
C2 - 1381287
AN - SCOPUS:0026699760
VL - 70
SP - 811
EP - 819
JO - Cell
JF - Cell
SN - 0092-8674
IS - 5
ER -