Missense Mutation in LAMA3 Associated with Herlitz Junctional Epidermolysis Bullosa in a Pakistani Family

Junctional Epidermolysis Bullosa (JEB affects intra-lamina Iucida of skin and is an exclusively autosomal recessive mechanobullous disorder. Its major subtypes include Herlitz (H-JEB; MIM#226700) and non Herlitz-JEB (nH-JEB: MIN#226650). the former being the lethal form. Genetic causes of this disease include mutations in genes encoding for laminin-332 (LM-332) i.e. LAM43, LAMB3 and LAMC2. The objective of the current study was to elucidate the genetic basis of JEB patients in a consanguineous family of Pakistani origin. Screening of exons and intron-exon boundaries of LAMA3. LAMB3 and LAMC2 was carried out. Normal as well as carriers of the affected family, along with 99 healthy control individuals of the same ethnicity, were screened by PCR-RFLP and dye terminator cycle sequencing. Sequence analyses of the patient revealed homozygosity for a missense variant c.4540G>C (p.D1514H) in LAMA3, which encodes the alpha chain of LM-332 (a skin adhesion protein) that is of importance for cell surface binding. The majority of cases with H-JEB are caused by truncating mutations with loss of LM-332 whereas missense mutations are extremely rare. These results add to the mutation spectrum associated with JEB and improve our understanding of LAMA3 in epidermal-dermal integrity.