A Missense Variant Affecting the N-Terminal Domain of the Laminin-332 β3 Chain Results in a Distinct Form of Junctional Epidermolysis Bullosa With Altered Granulation Tissue Response and No New Blistering: A Second Family Report

Abstract

Junctional epidermolysis bullosa (JEB) is a rare genodermatosis characterized by fragility of the skin and mucous membranes due to alterations in the dermal epidermal junction. This condition manifests as mechanically induced bullous lesions that heal with hypertrophic granulation tissue and/or atrophic scars. Here, we report two brothers carrying a homozygous LAMB3 missense variant, p.Gly254Asp, which affects the N-terminal end of the laminin-332 (LM332) β3 chain, previously described in another JEB family sharing a common ethnic origin and LAMB3 haplotype with the siblings reported here. Moreover, all affected patients with p.Gly254Asp mutation from both families exhibits a distinct phenotype consisting of a few localized long-standing skin lesions characterized by excessive granulation tissue formation or keloid scars, without new blistering, and associated with amelogenesis imperfecta. Our patients also showed nail dystrophy, expanding the phenotypic spectrum and confirming the peculiar role of the N-terminal end of the β3 chain in regulating the granulation tissue response associated with the wound healing process.

Keywords: LAMB3; JEB; granulation tissue; laminin‐332; wound repair.

FIGURE 1

(A) Family pedigree, with the probands IV.6 and IV.8, born from consanguineous parents; (B) localization of the Gly254Asp variant in LAMB3 gene and protein. Schematic representation of the LN (laminin N terminal), LE1 (laminin EGF‐like motif 1), LCC (laminin coiled coil) domains. The homozygous nucleotide variant was detected by WES (SureSelect Focused Exome Panel; Agilent Technologies, Waldbrron, Germany); (C) location of the Gly254Asp variant, highlighted in red, in the model of LAMB3 protein structure. The thermodynamic stability of the protein carrying this variant was investigated through FoldX, a protein design algorithm that uses an empirical force field (https://foldxsuite.crg.eu/), as described by Biagini et al. [2]. A model of the wild‐type LAMB3 structure was obtained through the automated protein homology‐modeling server SwissModel (https://swissmodel.expasy.org/). The difference in free‐energy (ΔΔG) between the mutant and wild‐type protein (ΔG _mut, ΔG _wt) was assessed and resulted equal to 10.8873, indicative of a highly destabilizing effect of the variant on the protein structure; (D) structure of LM332: A trimeric molecule shaped like a cross, with the long arm formed by the twisted C‐terminal ends of the α, β, and γ chains, and three short arms consisting of their N‐terminal ends.

FIGURE 2

Clinical features of the patients showing: (A) absence of several permanent teeth, tooth hypoplasia, periodontitis, and severe enamel hypo/dysplasia; (B) onychodystrophy with paronychia; (C) prominent granulation tissue in a chronic ulcerative lesion of groin; (D) toenail dystrophy and bilateral absence of the great toenails.