LAMB3 – Epidermolysis Bullosa

The LAMB3 gene encodes the β3 subunit of laminin-332, a critical component of the epidermal basement membrane zone. Biallelic loss-of-function variants in LAMB3 cause autosomal recessive epidermolysis bullosa, characterized by skin fragility and blister formation.

Multiple case series and cohort studies have identified at least 265 unrelated probands harboring homozygous or compound heterozygous truncating, frameshift, and splice-site variants in LAMB3 (PMID:8824879; PMID:9160387; PMID:16473856). The recurrent nonsense variants c.124C>T (p.Arg42Ter) and c.1978C>T (p.Arg660Ter) arise at CpG dinucleotides as mutational hotspots (PMID:8824879).

Segregation analysis in 14 Herlitz JEB families demonstrated co-segregation of homozygous and compound heterozygous LAMB3 variants with disease in affected sibships (PMID:8824879). Prenatal genetic testing in 15 at-risk families accurately predicted affected fetuses, later confirmed by fetal skin biopsy (PMID:9160387).

Clinically, LAMB3-related EB presents in early infancy with widespread blistering at the level of the lamina lucida, mucosal erosions, recurrent skin infections (HP:0002719), and nail dystrophy (HP:0008404).

Functional modeling in vivo and in vitro underpins a loss-of-function mechanism. A spontaneous murine LamB3 IAP insertion recapitulates junctional EB symptoms (PMID:9271670), and gentamicin-mediated readthrough of premature stop codons restores laminin-332 assembly, epidermal adhesion, and integrin α6β4 polarization in patient keratinocytes (PMID:29946029).

Collectively, the abundant and concordant genetic and experimental data fulfill ClinGen criteria for a definitive gene-disease relationship. LAMB3 molecular testing should be incorporated into diagnostic workflows for EB, guiding genetic counseling, prenatal diagnosis, and potential targeted therapies.

References

• Human molecular genetics • 1996 • Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa. PMID:8824879
• Prenatal diagnosis • 1997 • Mutation-based prenatal diagnosis of Herlitz junctional epidermolysis bullosa. PMID:9160387
• Journal of medical genetics • 2006 • Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. PMID:16473856
• 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
• 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
• 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

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