Missense mutation in LAMA3 associated with herlitz junctional epidermolysis bullosa in a pakistani family

Junctional epidermolysis bullosa (jeb) affects intra-lamina lucida 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; mim#226650),the former being the lethal form. genetic causes of this disease include mutations in genes encoding for laminin-332 (lm-332) i.e. lama3,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. copyright © 2012 zoological society of pakistan.