LAMB3 – Junctional epidermolysis bullosa Herlitz type

Junctional epidermolysis bullosa Herlitz type (H-JEB) is a lethal autosomal recessive genodermatosis characterized by widespread skin and mucosal blistering due to failure of the epidermal basement membrane adhesion complex. Biallelic loss-of-function variants in LAMB3, encoding the β3 chain of laminin-332, underlie this severe phenotype. Affected neonates present at birth with extensive erosions, mucosal involvement, and life expectancy typically under 6 months without intervention.

Initial molecular characterization in 12 unrelated H-JEB patients identified LAMB3 variants in 8 probands, including recurrent nonsense mutations p.Arg635Ter (c.1903C>T) and p.Gln373Ter, and novel missense and frameshift alleles (PMID:15538630). The homozygous p.Arg635Ter allele accounted for five cases, while three additional probands carried it in compound heterozygosity, correlating with survival beyond 6 months in female infants.

Segregation analyses across 14 families demonstrated that each affected individual harbored two premature termination codons in LAMB3, with R42X (c.124C>T) and R635X (c.1903C>T) hotspots comprising over 50% of mutant alleles. Haplotype mapping confirmed independent occurrence on distinct genetic backgrounds, supporting de novo and inherited mutational events (PMID:8824879).

Functional assays reveal absent laminin-332 deposition in patient keratinocytes by immunofluorescence and immunoblotting. A murine LamB3 intracisternal-A particle insertion model recapitulates subepidermal blistering and hemidesmosome defects seen in H-JEB, confirming loss of β3 chain function as the pathogenic mechanism (PMID:9271670).

Therapeutic proof-of-concept was provided by gentamicin-mediated readthrough of LAMB3 nonsense alleles, including c.1903C>T (p.Arg635Ter) and c.870T>A (p.Cys290Ter). Gentamicin treatment restored full-length laminin β3, reassembled laminin-332, and corrected adhesion and motility defects in keratinocytes and 3D skin equivalents (PMID:29946029).

These collective data fulfill ClinGen criteria for a definitive gene–disease relationship between LAMB3 and H-JEB through robust genetic evidence in multiple families, segregation confirmation, and concordant functional validation in cellular and animal models. Key take-home: genetic testing for LAMB3 is essential for accurate diagnosis, prognosis, genetic counseling, and consideration of emerging readthrough therapies in lethal H-JEB.

References

• Human molecular genetics • 1996 • Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa PMID:8824879
• Human genetics • 2005 • Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease. PMID:15538630
• Mammalian genome • 1997 • IAP insertion in the murine LamB3 gene results in junctional epidermolysis bullosa. PMID:9271670
• Proceedings of the National Academy of Sciences of the United States of America • 2018 • Gentamicin induces LAMB3 nonsense mutation readthrough and restores functional laminin 332 in junctional epidermolysis bullosa. PMID:29946029
• The Journal of investigative dermatology • 2016 • Genotype, Clinical Course, and Therapeutic Decision Making in 76 Infants with Severe Generalized Junctional Epidermolysis Bullos PMID:27375110

Evidence Based Scoring (AI generated)