TY - JOUR
T1 - Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients
T2 - Genetic and functional analyses
AU - Coulombe, Pierre A.
AU - Hutton, M. Elizabeth
AU - Letal, Anthony
AU - Hebert, Adelaide
AU - Paller, Amy S.
AU - Fuchs, Elaine
N1 - Funding Information:
with Koebner EBS skin biopsies. We also thank Dr. Ervin Epstein (Veteran’s Hospital, San Francisco) for sharing with us his results on EBSrestrictionfragment linkedpolymorphismstudies. WethankGraz-ina Traska for her technical assistance in cell culture. We also thank Diane Gingras (laboratory of Dr. Moise Bendayan, University of Montreal, Canada) for thin sectioning of resin-embedded EBS samples. This work was supported by grants from the Howard Hughes Medical Institute and the National Institutes of Health (AR27883). P. A. C. is the recipient of a Centennial Postdoctoral Fellowship from the Canadian Medical Research Council. A. L. was the recipient of Medical Scientist Training Program and Cancer Biology Training Program fellowships from the NIH and NCI, respectively.
PY - 1991/9/20
Y1 - 1991/9/20
N2 - Previously we demonstrated that transgenic mice expressing mutant basal epidermal keratin genes exhibited a phenotype resembling a group of autosomal dominant human skin disorders known as epidermolysis bullosa simplex (EBS). EBS diseases affect ∼1: 50,000 and are of unknown etiology, although all subtypes exhibit blistering arising from basal cell cytolysis. We now demonstrate that two patients with spontaneous cases of Dowling-Meara EBS have point mutations in a critical region in one (K14) of two basal keratin genes. To demonstrate function, we engineered one of these point mutations in a cloned human K14 cDNA, and showed that a K14 with an Arg-125→Cys mutation disrupted keratin network formation in transfected keratinocytes and perturbed filament assembly in vitro. Since we had previously shown that keratin network perturbation is an essential component of EBS diseases, these data suggest that the basis for the phenotype in this patient resides in this point mutation.
AB - Previously we demonstrated that transgenic mice expressing mutant basal epidermal keratin genes exhibited a phenotype resembling a group of autosomal dominant human skin disorders known as epidermolysis bullosa simplex (EBS). EBS diseases affect ∼1: 50,000 and are of unknown etiology, although all subtypes exhibit blistering arising from basal cell cytolysis. We now demonstrate that two patients with spontaneous cases of Dowling-Meara EBS have point mutations in a critical region in one (K14) of two basal keratin genes. To demonstrate function, we engineered one of these point mutations in a cloned human K14 cDNA, and showed that a K14 with an Arg-125→Cys mutation disrupted keratin network formation in transfected keratinocytes and perturbed filament assembly in vitro. Since we had previously shown that keratin network perturbation is an essential component of EBS diseases, these data suggest that the basis for the phenotype in this patient resides in this point mutation.
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U2 - 10.1016/0092-8674(91)90051-Y
DO - 10.1016/0092-8674(91)90051-Y
M3 - Article
C2 - 1717157
AN - SCOPUS:0025861772
SN - 0092-8674
VL - 66
SP - 1301
EP - 1311
JO - Cell
JF - Cell
IS - 6
ER -