LAMA3 – Junctional Epidermolysis Bullosa

Laminin alpha-3 (LAMA3) is implicated in autosomal recessive junctional epidermolysis bullosa (JEB), characterized by extensive skin and mucosal blistering due to defective basement membrane adhesion. The first evidence of LAMA3 involvement was the identification of a homozygous nonsense variant c.6808C>T (p.Arg2270Ter) in a patient with lethal Herlitz JEB, confirming loss-of-function as a disease mechanism ([PMID:7633458]).

Subsequent case series have described a broad allelic spectrum in LAMA3 across unrelated families, including frameshift (e.g., c.6505del (p.Val2169fs)) and splice-site variants leading to premature termination or exon skipping, and rare missense substitutions impacting protein folding (e.g., p.Gly1506Glu) in the adhesion G domain ([PMID:12943669]). Compound heterozygosity for null and hypomorphic alleles gives rise to intermediate non-Herlitz phenotypes, while homozygous PTCs correlate with early lethality.

Segregation analysis in multiple consanguineous and outbred pedigrees has demonstrated co-segregation of bi-allelic LAMA3 variants with JEB phenotypes, with no additional phenocopies reported. Heterozygous carriers exhibit subtle enamel pitting due to haploinsufficiency, underscoring dosage sensitivity of laminin-332 ([PMID:27827380]).

Functional studies in patient keratinocytes show ER retention of truncated alpha-3 chains and absence of secreted laminin-332, resulting in basement membrane fragility and blister formation. Spontaneous read-through of specific PTCs (e.g., R943X) restores full-length protein and improves cellular adhesion, highlighting sequence context effects on termination efficiency ([PMID:21693480]).

A landmark ex vivo gene therapy trial regenerated a fully functional epidermis in a JEB patient by transducing autologous keratinocyte stem cells with a corrective LAMA3 transgene, achieving durable laminin-332 expression and clinical remission without clonal selection ([PMID:29144448]).

Collectively, multi-family genetic evidence and concordant functional assays over three decades establish a definitive role for LAMA3 in JEB. Genetic testing for LAMA3 PTC and missense variants informs diagnosis, carrier screening, and personalized therapeutic strategies. Key Take-home: LAMA3 variant analysis is essential for accurate JEB diagnosis and enables targeted gene-based interventions.

References

• Human molecular genetics • 1995 • A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in lethal (Herlitz) junctional epidermolysis bullosa. PMID:7633458
• Biochemical and biophysical research communications • 2003 • A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa. PMID:12943669
• Journal of medical genetics • 2011 • Efficiency of translation termination in humans is highly dependent upon nucleotides in the neighbourhood of a (premature) termination codon. PMID:21693480
• Nature • 2017 • Regeneration of the entire human epidermis using transgenic stem cells. PMID:29144448

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