Mutations in EXPH5 result in autosomal recessive inherited skin fragility.

[epidermolysis bullosa simplex]

Several different genes have been implicated in the pathophysiology of inherited blistering skin diseases . Recently , autosomal recessive loss -of-function mutations in EXPH 5 (encoding exophilin-5 , also known as Slac 2 -b , a protein involved in intracellular vesicle transport ) were identified in a new mechanobullous disease resembling a form of epidermolysis bullosa simplex (EBS ). Here , we searched for mutations in EXPH 5 in a 4 -year -old white boy with EBS in whom initial Sanger sequencing of known genes implicated in intraepidermal skin fragility failed to identify pathogenic mutations . Transmission electron microscopy of rubbed nonlesional patient skin revealed disruption of keratinocytes in the lower epidermis with cytolysis and acantholysis , keratin filament clumping and prominent perinuclear cytoplasmic vesicles , and provided the clue to the candidate gene pathology . Sanger sequencing of genomic DNA showed compound heterozygosity for two new mutations in EXPH 5 , c .1947 dupC (p .Pro 649 fsPro *11 ) and c .2249 C >A (p .Ser 750 *). Immunofluorescence microscopy of patient skin showed a complete absence of exophilin-5 labelling . This case represents the third pedigree with EXPH 5 mutations resulting in inherited skin fragility . The clinical and molecular data expand genotype-phenotype correlation in this new form of EBS and demonstrate the important role of exophilin-5 in keratinocyte cell biology .