Extent of laminin-5 assembly and secretion effect junctional epidermolysis bullosa phenotype.
J Exp Med
; 187(8): 1273-83, 1998 Apr 20.
Article
em En
| MEDLINE
| ID: mdl-9547338
ABSTRACT
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 alpha3beta3gamma2 heterotrimer assembles intracellularly via a beta3gamma2 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Moléculas de Adesão Celular
/
Epidermólise Bolhosa Juncional
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Adult
/
Child
/
Humans
/
Infant
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
1998
Tipo de documento:
Article
País de afiliação:
Estados Unidos