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.

Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants

“…Examples of such recurrent mutations in LAMB3 include: Q1083X, detected in patients of Middle Eastern origin; Q166X and W610X, seen in patients of Japanese origin; 31insC (previously reported as 29insC); and W143X, noted in patients of Italian origin. [26][27][28][29][30][31] One recurrent mutation, R650X, has been observed in the LAMA3 gene in Pakistani patients. 32 Reports of recurrent mutations in the LAMC2 gene include R95X, observed in patients of Italian origin, and Q46X, seen in patients in the Middle East region.…”

A truncating mutation in the laminin-332α chain highlights the role of the LG45 proteolytic domain in regulating keratinocyte adhesion and migration

“…JEB‐H is mostly caused by premature termination codon mutations, which lead to mRNA decay and lack of protein synthesis . JEB‐nH usually results from combinations of premature termination codon (PTC) mutations with missense or splice site mutations, which allow expression of a residual amount of partially functional laminin‐332 …”

Reply

“…A 100% childhood mortality was seen in the Australasian, Austrian, International, Italian, and Dutch JEB-H cohorts, together comprising a total of 69 patients with JEB-H, in which the oldest patient had died at the age of 10 years. [3][4][5][6][7][8] Because of the discrepancy of mortality seen in these cohorts, and those seen in the NEBR, Laimer et al 5 suggested that the long-term JEB-H survivors included in the NEBR might reflect a ''limited/restricted diagnostic validity/validation.'' Indeed, the NEBR uses merely nonmolecular diagnostic testing in combination with clinical findings to classify patients according to the 2008 classification report.…”