The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/4/1273/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 8, April 20, 1998 1273-1283

Articles

Extent of Laminin-5 Assembly and Secretion Effect Junctional Epidermolysis Bullosa Phenotype

Chihiro Matsui*, Phyllis Pereira*, C. Kathy Wang*, Charlotte F. Nelson*, Timothy Kutzkey*, Caroline Lanigan*, David Woodley{ddagger}, Masaaki Morohashi§, Elizabeth A. Welsh*, and Warren K. Hoeffler*

From the * Department of Dermatology, Stanford University School of Medicine, Stanford, California, 94305; {ddagger} Department of Dermatology, Northwestern University Medical School, Chicago, Illinois, 60611; and § Department of Dermatology, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, Toyama 930-01 Japan

Junctional epidermolysis bullosa (JEB) is an autosomal recessive skin blistering disease with both lethal and nonlethal forms, with most patients shown to have defects in laminin-5. We analyzed the location of mutations, gene expression levels, and protein chain assembly of the laminin-5 heterotrimer in six JEB patients to determine how the type of genetic lesion influences the pathophysiology of JEB. Mutations within laminin-5 genes were diversely located, with the most severe forms of JEB correlating best with premature termination codons, rather than mapping to any particular protein domain. In all six JEB patients, the laminin-5 assembly intermediates we observed were as predicted by our previous work indicating that the {alpha}3β3{gamma}2 heterotrimer assembles intracellularly via a β3{gamma}2 heterodimer intermediate. Since assembly precedes secretion, mutations that disrupt protein–protein interactions needed for assembly are predicted to limit the secretion of laminin-5, and likely to interfere with function. However, our data indicate that typically the most severe mutations diminish mRNA stability, and serve as functional null alleles that block chain assembly by resulting in either a deficiency (in the nonlethal mitis variety) or a complete absence (in lethal Herlitz-JEB) of one of the chains needed for laminin-5 heterotrimer assembly.

Address correspondence to Warren K. Hoeffler, Ph.D., Department of Dermatology, MSLS, Room P210, Stanford University School of Medicine, Stanford, CA 94305. Phone: 650-723-7843; Fax: 650-723-8762; E-mail: hf.wkh{at}forsythe.stanford.edu

1Abbreviations used in this paper: 1-D, 1-dimensional; BMZ, basement membrane zone; EB, epidermolysis bullosa; JEB, junctional EB; PTC, premature termination codon; SFM, serum-free media.


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