A homozygous nonsense mutation in the  3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa

Abstract

The inherited mechanobullous disorder, junctional epidermolysis bullosa (JEB), is characterized by extensive blistering and erosions of the skin and mucous membranes. The diagnostic hallmarks of JEB include ultrastructural abnormalities in the hemidesmosomes of the cutaneous basement membrane zone, as well as an absence of staining with antibodies against the anchoring filament protein, laminin 5. Therefore, the three genes encoding alpha 3, beta 3 and gamma 2 chains of laminin 5, known as LAMA3, LAMB3 and LAMC2, are candidate genes for JEB. We have previously demonstrated mutations in the LAMB3 and LAMC2 genes in several families with JEB. We initiated mutation analysis from an affected child by PCR amplification of individual LAMA3 exons, followed by heteroduplex analysis. Nucleotide sequencing of heteroduplexes identified a homozygous nonsense mutation within domain I/II of the alpha 3 chain. These findings provide the first evidence that nonsense mutations within the LAMA3 gene are also involved in the pathogenesis of JEB, and indicate that mutations of all three genes of laminin 5 can result in the JEB phenotype.

Sole Expression of Laminin γhain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung Adenocarcinomas

“…1,5,6) Mutation or deletion of the LN-5 genes (LAMA3, LAMB3, and LAMC2) is associated with epidermolysis bullosa, a lethal skin blistering disease. [7][8][9] LN-5 strongly promotes adhesion, migration, and scattering of various types of cultured cells compared with other extracellular matrix proteins. 4,10,11) The expression of LN-5 in tumor cells is stimulated by growth factors and a tumor promoter in vitro.…”

Cloning and Complete Primary Structure of the Mouse Laminin α3 Chain

“…Mutations in the genes encoding laminin 5, including its ␣3 chain, have been shown to underlie the junctional forms of epidermolysis bullosa, a recessive inherited skin disorder characterized by dysadhesion of the epidermis from dermis (Kivirikko et al (1995) and references therein; Vidal et al (1995)). …”

Genetic Predisposition to Cutaneous Squamous Cell Carcinoma

“…Due to the severe blistering and fragile internal mucosae, most infants die early. JEB-other (includes localized and generalized non-Herlitz JEB and JEB with pyloric atresia), may involve type XVII collagen or 64 integrin gene in addition to laminin-332 Kivirikko et al, 1995;Vidal et al, 1995). Patients usually survive to adulthood in generalized non-Herlitz JEB as severity of the disease decrease with age.…”