A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa

Laminin-5 Mutational Analysis in an Italian Cohort of Patients with Junctional Epidermolysis Bullosa

“…All described splice site mutations have been shown to allow the synthesis of variably reduced amounts of either internally deleted or mutant full-length laminin-5 chain mRNA molecules (Posteraro et al, 1998;Castiglia et al, 2001; this study). The missense mutation G1506E in LAMA3 did not affect mRNA stability but interfered with the proper folding of the fourth carboxy-terminal globular domain (LG4) resulting in the retention of most of the mutated a3 polypeptide within the endoplasmic reticulum (Scaturro et al, 2003). Consequently, in all non-H JEB cases detectable amounts of mutant laminin-5 were secreted, underwent physiologic extracellular maturation and correctly localized within the cutaneous BMZ, as attested by radioimmunoprecipitation of cultured keratinocyte media and/or immunofluorescence analysis of skin biopsies.…”

“…JEB was diagnosed on the basis of clinical features, immunofluorescence antigen mapping, and ultrastructural examination of skin biopsies (Castiglia et al, 2001;Gardella et al, 2002;Scaturro et al, 2003). In most patients, a skin biopsy was also processed for keratinocyte cultures as described (Zambruno et al, 1995).…”

“…These features are the hallmarks of the lethal Herlitz JEB variant (H JEB, OMIM 226700) (Pulkkinen et al, 1997b;Bauer et al, 2002). Other mutations, in most cases missense or in frame deletions in one or both alleles of the laminin-5 genes, cause a reduced expression of aberrant laminin-5 molecules that retain a residual biological activity, which results in the limited tendency to blistering distinctive of the mild non-Herlitz JEB (non-H JEB, OMIM 226650) (Posteraro et al, 1998;Castiglia et al, 2001, Nakano et al, 2002aScaturro et al, 2003). Homozygous premature termination codon (PTC) mutations in laminin-5 genes, however, have been associated to either lethal and non-lethal JEB phenotypes McGrath et al, 1999;Gache et al, 2001;Nakano et al, 2002a).…”

Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease

“…3 Summary of the known mutations in the laminin-5 genes. The molecular structure of the unprocessed laminin-5 molecule based on Nakano et al (2002a) and modified according to structural data from LION biosciences (a3, Q16787; b3, Q13751; c2, Q13753), Ensembl (a3, ENSP00000269217; b3, ENSP00000261451; c2, ENSP00000264144) and NCBI (b3, NM_000228; c2, NM_005562) and the location of all known mutations (Human Gene Mutation Database, http://archive.uwc m.ac.uk/uwcm/mg/ hgmd0.html; CserhalmiFriedman et al 2002;Gache et al 2001;Klausegger et al 2001;Nakano et al 2000Nakano et al , 2002aNakano et al , 2002bScaturro et al 2003;Spirito et al 2001) is shown. The mutations are listed with the generally accepted designation and numbering system.…”

“…The conclusion that the absence of any of the three subunits prevents the assembly to a functional laminin-5 molecule, resulting in H-JEB, is further supported by recent studies on transgenic or naturally occurring mice that lack the expression of LAMA3, LAMB3 or LAMC2 and present with a lethal blistering phenotype reminiscent of H-JEB (Kuster et al 1997;Meng et al 2003;Ryan et al 1999). Figure 3 gives an overview of all presently known mutations in the coding and splicingrelevant regions of the laminin-5 genes associated with JEB and their location in the polypeptide chains, as collected from the Human Gene Mutation Database (http://archive.uwcm.ac.uk/uwcm/mg/hgmd0.html) and published reports (Cserhalmi-Friedman et al 2002;Gache et al 2001;Klausegger et al 2001;Nakano et al 2000Nakano et al , 2002aNakano et al , 2002bScaturro et al 2003;Spirito et al 2001). The overwhelming majority of these mutations reside in the gene LAMB3, predominantly in the portion encoding the amino-terminal short arm of the polypeptide.…”