LAMB3 – Generalized Junctional Epidermolysis Bullosa Non-Herlitz Type

Generalized junctional epidermolysis bullosa non-Herlitz type (GABEB; MONDO:0019307) is an autosomal recessive blistering disorder characterized by skin fragility, widespread atrophic changes, alopecia, and nail dystrophy. Mutations in LAMB3, encoding the β3 chain of laminin-332, account for a subset of GABEB cases, with the remainder predominantly due to COL17A1 defects.

Inheritance is autosomal recessive, with compound heterozygous or homozygous variants in LAMB3 identified in multiple unrelated probands. A Japanese patient carried a splice acceptor mutation c.1977-2A>G and a 94-bp deletion c.2702-29del94 leading to exon 19 skipping and mRNA instability (PMID:10951252). Two siblings with GABEB exhibited characteristic features and carried LAMB3 or COL17A1 mutations demonstrating familial segregation (PMID:9487212). A study of three additional patients from two families revealed LAMB3 missense and premature termination mutations (e.g., c.628G>A (p.Glu210Lys)) causing mRNA decay and aberrant splicing (PMID:9690563).

The variant spectrum includes splice-site (c.1977-2A>G, c.628G>A), missense (c.628G>A (p.Glu210Lys)), frameshift (c.1365_1366del (p.Asn456fs)), and small deletions (c.2702-29del94) in LAMB3. Recurrent hotspots have been noted in lethal H-JEB but are distinct from non-lethal GABEB alleles.

Segregation analysis supports pathogenicity: affected siblings in two families and compound heterozygosity in unrelated individuals confirm recessive transmission with at least one additional affected relative per kindred.

Functional studies demonstrate exon skipping and enhanced mRNA decay in patient cells, consistent with reduced laminin-332 expression. A LamB3 knockout mouse model exhibits subepidermal blistering and hypoplastic hemidesmosomes, mirroring human JEB phenotypes (PMID:9271670).

No significant conflicting reports disputing LAMB3’s role in GABEB have been identified. The collective genetic and experimental data fulfill criteria for a strong gene–disease association.

Key take-home: LAMB3 loss-of-function variants underlie autosomal recessive GABEB, with clear diagnostic utility for genetic testing and potential targets for future therapeutic interventions.

References

• The Journal of investigative dermatology • 2000 • Compound heterozygosity for a point mutation and a deletion located at splice acceptor sites in the LAMB3 gene leads to generalized atrophic benign epidermolysis bullosa. PMID:10951252
• Archives of dermatology • 1998 • Generalized atrophic benign epidermolysis bullosa in 2 siblings complicated by multiple squamous cell carcinomas. PMID:9487212
• Laboratory investigation; a journal of technical methods and pathology • 1998 • LAMB3 mutations in generalized atrophic benign epidermolysis bullosa: consequences at the mRNA and protein levels. PMID:9690563
• Mammalian genome : official journal of the International Mammalian Genome Society • 1997 • IAP insertion in the murine LamB3 gene results in junctional epidermolysis bullosa. PMID:9271670

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