title: Laminin 5 mutations in junctional epidermolysis bullosa: molecular basis of Herlitz vs. non-Herlitz phenotypes.
abstract: Junctional epidermolysis bullosa (JEB) is a group of heritable blistering diseases in which tissue separation occurs within the lamina lucida of the cutaneous basement membrane zone. Clinically, two broad subcategories have been recognized: The Herlitz variant (H-JEB; OMIM 226700) is characterized by early demise of the affected individuals, usually within the first year of life, while non-Herlitz (nH-JEB; OMIM 226650) patients show a milder phenotype with life-long blistering, yet with normal lifespan. In this study, we have examined a cohort of 27 families, 15 with Herlitz and 12 with non-Herlitz JEB, for mutations in the candidate genes, LAMA3, LAMB3, and LAMC2, encoding the subunit polypeptides of laminin 5. The mutation detection strategy consisted of PCR amplification of all exons in these genes, followed by heteroduplex scanning and nucleotide sequencing. We were able to identify pathogenic mutations in both alleles of each proband, the majority of the mutations being in the LAMB3 gene. Examination of the mutation database revealed that most cases with Herlitz JEB harbored premature termination codon (PTC) mutations in both alleles. In non-Herlitz cases, the PTC mutation was frequently associated with a missense mutation or a putative splicing mutation in trans. In three cases with putative splicing mutations, RT-PCR analysis revealed a repertoire of splice variants in-frame, predicting the synthesis of either shortened or lengthened, yet partly functional, polypeptides. These observations would explain the relatively mild phenotype in cases with splicing mutations. Collectively, these findings, together with the global laminin 5 mutation database, contribute to our understanding of the genotype/phenotype correlations explaining the Herlitz vs non-Herlitz phenotypes.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, 233 S. 10th Street, Suite 450 BLSB, Philadelphia, Pennsylvania, USA.
authors.forename: Aoi
authors.initials: A
authors.lastname: Nakano
authors.forename: Sheau-Chiou
authors.initials: SC
authors.lastname: Chao
authors.forename: Leena
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: Dedee
authors.initials: D
authors.lastname: Murrell
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: Ellen
authors.initials: E
authors.lastname: Pfendner
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D018388:Codon, Terminator / Q000235:genetics; D017931:DNA Primers; D016109:Epidermolysis Bullosa, Junctional / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D010641:Phenotype; D021122:Protein Subunits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000473:pathology; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D018388:Codon, Terminator; D017931:DNA Primers; D021122:Protein Subunits; D000097794:Kalinin