A RECURRENT HOMOZYGOUS NONSENSE MUTATION WITHIN THE LAMA3 GENE AS A CAUSE OF HERLITZ JUNCTIONAL EPIDERMOLYSIS-BULLOSA IN PATIENTS OF PAKISTANI ANCESTRY - EVIDENCE FOR A FOUNDER EFFECT

The anchoring filament protein laminin 5 is abnormally expressed in th e skin of patients with Herlitz junctional epidermolysis bullosa (H-JE B). In this study, we performed mutational analysis on genomic DNA fro m a H-JEB child of first-cousin Pakistani parents, and identified a ho mozygous C-to-T transition in the LAMA3 gene of laminin 5 resulting in a premature termination codon (CGA-TGA) on both alleles. This mutatio n, R650X, has been previously reported in two other seemingly unrelate d H-JEB individuals of Pakistani ancestry. Although this mutation map represent a mutational hotspot within the LAMA3 gene, haplotype analys is based on a silent intragenic polymorphism (GCC/GCG, alanine 429; Ge nBank no, L34155), and on three flanking microsatellite polymorphisms (D18S45, D18S478, and D18S480), suggests that a common ancestral allel e may be present in all three cases.