title: Laminin-5 mutational analysis in an Italian cohort of patients with junctional epidermolysis bullosa.
abstract: Junctional epidermolysis bullosa (JEB) is a rare genodermatosis characterized by dermal-epidermal separation that is caused by mutations in the genes encoding hemidesmosomal components and laminin-5, the major epithelial adhesion ligand. Here, we report on the mutational analysis of LAMA3, LAMB3, and LAMC2 genes encoding laminin-5 chains in 19 Italian patients, 11 affected with the severe Herlitz (H JEB) and eight with the mild non-Herlitz variant of JEB (non-H JEB). Eighteen mutations, seven of which were novel, were identified and their consequences analyzed at the mRNA and protein level. Premature termination codon mutations in both alleles of LAMB3 or LAMC2 genes were found in nine of the 11 H JEB patients, with a prevalence of mutations in LAMC2. In one case, a homozygous frameshift mutation in LAMB3 was associated to illegitimate splicing leading to non-H JEB. One H JEB patient showed a large intragenic duplication within LAMC2, a genetic defect so far uncovered in laminin-5 genes. Splicing or missense mutations, were prevalent in non-H JEB patients. Collectively, five mutations appeared to be frequent in laminin-5 JEB patients: R635X, 29insC, E210K, W143X in LAMB3 and R95X in LAMC2. These recurrent mutations account for approximately 44% of laminin-5 JEB alleles in Italian patients.
authors.affiliation: Department of Clinical and Molecular Pathology, IDI-IRCCS, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Posteraro
authors.forename: Naomi
authors.initials: N
authors.lastname: De Luca
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.forename: May
authors.initials: M
authors.lastname: El Hachem
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gobello
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tadini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
mesh_terms: D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics; D018389:Codon, Nonsense; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D016109:Epidermolysis Bullosa, Junctional / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D007558:Italy; D007797:Laminin / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D018389:Codon, Nonsense; D007797:Laminin; D022821:RNA Splice Sites; D012333:RNA, Messenger; D000097794:Kalinin; C400567:LAMC2 protein, human; C095567:laminin alpha 3