LAMC2 – Junctional Epidermolysis Bullosa

Junctional epidermolysis bullosa (JEB) is a rare, autosomal recessive blistering disorder characterized by tissue separation within the lamina lucida of the cutaneous basement membrane. The LAMC2 gene encodes the γ2 subunit of laminin-332, a critical component of hemidesmosomal anchoring complexes. Biallelic LAMC2 variants cause both lethal Herlitz and milder non-Herlitz forms of JEB through loss of function.

Initial human case reports identified compound heterozygous and homozygous truncating LAMC2 alleles in neonates with fatal blistering, confirming autosomal recessive inheritance [PMID:24533970; PMID:38648026]. A landmark study described a splice acceptor mutation, c.1067-1G>A, in two unrelated patients, establishing aberrant splicing as a pathogenic mechanism [PMID:8012393]. Larger cohorts from the Middle East and Italy encompassed 19 affected relatives across eight families, each harboring biallelic premature termination codon variants [PMID:11907499; PMID:15373767]. No heterozygous carriers manifest disease, consistent with a requirement for complete loss of γ2 function.

Collectively, more than 30 probands across multiple studies have been reported with LAMC2 mutations, comprising at least 8 splice-site, 20 premature termination codon, and numerous missense changes [PMID:8012393; PMID:15373767]. Variants include recurrent splice donor alleles (e.g., c.2014+1G>A) and diverse indels leading to early termination. Homozygous PTC alleles correlate with lethal Herlitz JEB, whereas compound heterozygosity for a PTC and a hypomorphic splice variant yields non-lethal phenotypes [PMID:11810295]. Missense substitutions cluster in the N-terminal domain of γ2, suggesting domain-specific functional tolerance. Large intragenic deletions have also been documented, and pathogenic allele frequencies remain extremely low in population databases.

Functional assays in patient keratinocytes demonstrate markedly reduced LAMC2 mRNA stability and impaired secretion of laminin-332 heterotrimers [PMID:11564184]. Transient transfection of mutant γ2 cDNAs into γ2-null keratinocytes showed that in-frame deletions upstream of the proteolytic cleavage site permit partial assembly and deposition, whereas C-terminal truncations abolish heterotrimer formation. Deficient laminin-332 deposition disrupts hemidesmosome integrity and epidermal adhesion in vitro. Electron microscopy of patient skin reveals subepidermal clefting with absent anchoring filaments, mirroring in vitro findings. Rescue experiments with wild-type γ2 constructs restore matrix deposition and adhesion, affirming loss of function as the molecular mechanism.

Integration of genetic segregation and functional restoration data meets ClinGen criteria for a Definitive gene–disease association. Robust autosomal recessive segregation across multiple families, a diverse loss-of-function variant spectrum, and concordant in vitro rescue assays underpin this classification. No conflicting evidence has been reported. While additional in vivo models could further detail pathogenic pathways, current evidence suffices for diagnostic and prognostic use. LAMC2 sequencing should be included in comprehensive JEB panels to enable precise diagnosis, genetic counseling, and early management.

Key Take-home: Biallelic loss-of-function variants in LAMC2 are definitively causative for autosomal recessive junctional epidermolysis bullosa; inclusion in diagnostic panels is critical for accurate identification and management of affected patients.

References

• Nature genetics • 1994 • Mutations in the gamma 2 chain gene (LAMC2) of kalinin/laminin 5 in the junctional forms of epidermolysis bullosa. PMID:8012393
• The Journal of investigative dermatology • 2001 • Novel mutations in the LAMC2 gene in non-Herlitz junctional epidermolysis bullosa: effects on laminin-5 assembly, secretion, and deposition. PMID:11564184
• The Journal of dermatology • 2014 • Novel compound heterozygous mutation in LAMC2 genes (c.79G>A and 382insT) in Herlitz junctional epidermolysis bullosa. PMID:24533970
• Journal of the American Academy of Dermatology • 2002 • Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families. PMID:11907499
• The Journal of investigative dermatology • 2004 • Laminin-5 mutational analysis in an Italian cohort of patients with junctional epidermolysis bullosa. PMID:15373767
• The American Journal of dermatopathology • 2024 • Junctional Epidermolysis Bullosa Linked to Homozygous Mutation in LAMC2 Gene: A Case Report With Eosinophil-Rich Inflammatory Infiltrate. PMID:38648026
• Human genetics • 2002 • Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes. PMID:11810295

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