title: A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa.
abstract: Laminin-5 is the major adhesion ligand for epithelial cells. Mutations in the genes encoding laminin-5 cause junctional epidermolysis bullosa (JEB), a recessive inherited disease characterized by extensive epithelial-mesenchymal disadhesion. We describe a JEB patient compound heterozygote for two novel mutations in the gene (LAMA3) encoding the laminin alpha3 chain. The maternal mutation (1644delG) generates mRNA transcripts that undergo nonsense-mediated decay. The paternal mutation results in the Gly1506-->Glu substitution (G1506E) within the C-terminal globular region of the alpha3 chain (G domain). Mutation G1506E affects the proper folding of the fourth module of the G domain and results in the retention of most of the mutated polypeptide within the endoplasmic reticulum (ER). However, scant amounts of the mutated laminin-5 are secreted, undergo physiologic extracellular maturation, and correctly localize within the cutaneous basement membrane zone in patient's skin. Our findings represent the first demonstration of an ER-retained mutant laminin-5 leading to a mild JEB phenotype.
authors.affiliation: Laboratory of Molecular and Cell Biology, Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Scaturro
authors.forename: Patrizia
authors.initials: P
authors.lastname: Posteraro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mastrogiacomo
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Zaccaria
authors.forename: Naomi
authors.initials: N
authors.lastname: De Luca
authors.forename: Cinzia
authors.initials: C
authors.lastname: Mazzanti
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000235:genetics*; D002478:Cells, Cultured; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D004721:Endoplasmic Reticulum / Q000378:metabolism; D016109:Epidermolysis Bullosa, Junctional / Q000235:genetics*; D005220:Fathers; D005260:Female; D005808:Genes, Recessive; D018698:Glutamic Acid / Q000737:chemistry; D005998:Glycine / Q000737:chemistry; D006579:Heterozygote; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007797:Laminin / Q000737:chemistry* / Q000235:genetics; D008297:Male; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009035:Mothers; D009154:Mutation; D020125:Mutation, Missense; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D011233:Precipitin Tests; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D018389:Codon, Nonsense; D018698:Glutamic Acid; D005998:Glycine; D007797:Laminin; D010455:Peptides; D012333:RNA, Messenger; D000097794:Kalinin; C095567:laminin alpha 3