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J. Exp. Med.,
Volume 187, Number 8, April 20, 1998 1273-1283
By
From the * Department of Dermatology, Stanford University School of Medicine, Stanford, California,
94305; 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 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
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heterotrimer assembles intracellularly via a 32 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.
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