LAMA3 – Herlitz Junctional Epidermolysis Bullosa

LAMA3 encodes the alpha-3 chain of laminin-332, a critical component of the epidermal basement membrane. Herlitz junctional epidermolysis bullosa (H-JEB) is a rare, autosomal recessive genodermatosis presenting at birth with widespread skin and mucosal blistering due to tissue cleavage within the lamina lucida. Affected neonates exhibit absent laminin-332 by immunoepitope mapping and characteristic ultrastructural findings on electron microscopy.

A consanguineous Tunisian neonate developed immediate postnatal blistering and was homozygous for a novel nonsense variant p.Tyr955Ter in LAMA3. Skin biopsy revealed lamina lucida cleavage and complete absence of laminin-332. The infant succumbed to sepsis at 3 months of age (PMID:20881434).

In a cohort of 12 H-JEB patients, two novel LAMA3 truncating mutations, c.8755A>T (p.Lys2919Ter) and c.388G>T (p.Glu130Ter), were identified in unrelated families. Affected individuals lacked both truncated alpha-3 peptides and assembled laminin-5 on immunofluorescence, confirming loss-of-function (PMID:15538630).

Prenatal molecular analysis demonstrated a homozygous c.6808C>T (p.Arg2270Ter) LAMA3 mutation in an affected fetus. Direct mutation testing enabled exclusion of H-JEB in a subsequent pregnancy by chorionic villus biopsy, illustrating utility for genetic counseling (PMID:8530087).

Collectively, biallelic LAMA3 nonsense and frameshift variants result in absent laminin-332, skin cleavage within the lamina lucida, and lethal H-JEB. The concordant ultrastructural, immunohistochemical, and prenatal diagnostic data support a loss-of-function mechanism.

Key Take-home: Biallelic truncating LAMA3 variants cause autosomal recessive H-JEB via laminin-332 deficiency, facilitating accurate molecular diagnosis and prenatal counseling.

References

• Neonatology • 2011 • A novel LAMA3 mutation in a newborn with junctional epidermolysis bullosa herlitz type. PMID:20881434
• 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
• Genomics • 1995 • A homozygous nonsense mutation in the alpha 3 chain gene of laminin 5 (LAMA3) in Herlitz junctional epidermolysis bullosa: prenatal exclusion in a fetus at risk. PMID:8530087

Evidence Based Scoring (AI generated)