LAMB3 – Junctional Epidermolysis Bullosa

Junctional epidermolysis bullosa (JEB) is an autosomal recessive mechanobullous genodermatosis characterized by subepidermal blistering and mucocutaneous fragility at the level of the lamina lucida. Biallelic pathogenic variants in LAMB3, which encodes the β3 chain of laminin-332 (laminin-5), disrupt hemidesmosome assembly and are a leading cause of both lethal (Herlitz) and non-lethal JEB subtypes. The gene-disease association is supported by extensive clinical, genetic, and functional data that establish a definitive relationship.

Genetic evidence confirms autosomal recessive inheritance, with affected individuals harboring homozygous or compound heterozygous LAMB3 loss-of-function variants. Over 100 unrelated probands have been described with biallelic LAMB3 mutations leading to classic JEB phenotypes ([PMID:9205497]). Segregation analyses in multiple families show that heterozygous carriers are asymptomatic and that disease co-segregates with two mutant alleles. The variant spectrum includes nonsense (e.g., c.727C>T (p.Gln243Ter)) ([PMID:9326326]), frameshift (e.g., c.904del (p.Trp302fs)) ([PMID:9501007]), and splice-site changes (e.g., c.628G>A (p.Glu210Lys)) ([PMID:9501007]), all predicted to abolish β3 chain function.

Functional studies across cellular and animal models demonstrate that LAMB3 mutations abolish or severely reduce laminin-332 assembly. Patient keratinocytes lacking β3 are unable to form hemidesmosomes, resulting in impaired adhesion and colony formation, which can be fully restored by retroviral correction of LAMB3 ([PMID:9650620]). A spontaneous IAP insertion in murine LamB3 recapitulates the human blistering phenotype and hemidesmosomal defects, confirming the gene’s essential role in dermal-epidermal attachment ([PMID:9271670]).

No substantive conflicting evidence has been reported to refute the LAMB3–JEB association. Rare digenic cases affecting both COL17A1 and LAMB3 still require biallelic null variants in LAMB3 for clinical manifestation, underscoring its primary pathogenic role ([PMID:10577906]).

Integrating genetic and experimental data yields a coherent pathogenetic model in which LAMB3 loss-of-function leads to failed laminin-332 heterotrimer formation, hemidesmosome disruption, and clinically significant skin fragility. The reproducibility of phenotypes across diverse populations, together with functional rescue by gene correction, fulfills criteria for a definitive ClinGen classification.

Key Take-home: Molecular testing of LAMB3 enables precise diagnosis, carrier screening, prenatal assessment, and informs emerging therapies—such as readthrough of premature termination codons and gene therapy—to improve outcomes in JEB.

References

• The British Journal of Dermatology • 1997 • A recurrent laminin 5 mutation in British patients with lethal (Herlitz) junctional epidermolysis bullosa: evidence for a mutational hotspot rather than propagation of an ancestral allele. PMID:9205497
• American Journal of Human Genetics • 1997 • Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa. PMID:9326326
• Biochemical and Biophysical Research Communications • 1998 • Compound heterozygosity for an out-of-frame deletion and a splice site mutation in the LAMB3 gene causes nonlethal junctional epidermolysis bullosa. PMID:9501007
• Human Gene Therapy • 1998 • Corrective transduction of human epidermal stem cells in laminin-5-dependent junctional epidermolysis bullosa. PMID:9650620
• Mammalian Genome • 1997 • IAP insertion in the murine LamB3 gene results in junctional epidermolysis bullosa. PMID:9271670
• American Journal of Human Genetics • 1999 • Digenic junctional epidermolysis bullosa: mutations in COL17A1 and LAMB3 genes. PMID:10577906

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