ORIGINAL ARTICLE

Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants

R Varki, S Sadowski, E Pfendner, J Uitto

Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and the DebRA Molecular Diagnostics Laboratory, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, USA

Correspondence to:
Dr J Uitto
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, 233 South 10th Street, Suite 450 BLSB, Philadelphia, PA 19107, USA.; jouni.uitto{at}jefferson.edu

Introduction: Epidermolysis bullosa (EB), a group of autosomal heritable blistering diseases, is characterised by extensive phenotypic variability with considerable morbidity and mortality. EB is classified into distinct subtypes depending on the location of blistering within the cutaneous dermoepidermal basement membrane zone. Ten genes are known to harbour mutations in the major types of EB, and the level of expression of these genes within the cutaneous basement membrane zone and in extracutaneous tissues, as well as the types and combinations of the mutations, explain in general terms the phenotypic variability.

Methods: The DebRA Molecular Diagnostics Laboratory, established in 1996 and supported in part by the patient advocacy organisation DebRA of America, has analysed over 1000 families with different forms of EB.

Results: In total, 265 cases were submitted with the preliminary diagnosis of junctional or hemidesmosomal forms of EB. We found 393 mutant alleles in seven different genes, with 173 of the mutations being distinct and 71 previously unpublished.

Discussion: These findings attest to the clinical and molecular heterogeneity of the junctional and hemidesmosomal subtypes of EB. The results also reveal exceptions to the general rules on genotype-phenotype correlations, unusual phenotypes, and surprising genetics. Collectively, mutation analysis in different forms of EB provides the basis for improved classification with prognostic implications and for prenatal and preimplantation diagnosis in families at risk for recurrence of EB.

Abbreviations: BMZ, basement membrane zone; CV, chorionic villus; DEB, dystrophic epidermolysis bullosa; EB, epidermolysis bullosa; EB-MD, epidermolysis bullosa with muscular dystrophy; EB-PA, epidermolysis bullosa with pyloric atresia; EBS, epidermolysis bullosa simplex; GABEB, generalized atrophic benign epidermolysis bullosa; HEB, hemidesmosomal epidermolysis bullosa; JEB, junctional epidermolysis bullosa; LOC, laryngo-onychocutaneous; PTC, premature termination codon

Keywords: heritable skin diseases; blistering disorders; cutaneous basement membrane zone

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