Mutations in EXPH5 result in autosomal recessive inherited skin fragility

Several different genes have been implicated in the pathophysiology of inherited blistering skin diseases. Recently, autosomal recessive loss-of-function mutations in EXPH5 (encoding exophilin-5, also known as Slac2-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 EXPH5 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 EXPH5, c.1947dupC (p.Pro649fsPro11) and c.2249C>A (p.Ser750). Immunofluorescence microscopy of patient skin showed a complete absence of exophilin-5 labelling. This case represents the third pedigree with EXPH5 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. What's already known about this topic? Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous group of mechanobullous diseases. Recently, autosomal recessive mutations in EXPH5 (encoding exophilin-5, a protein involved in intracellular vesicle transport) were identified in a new clinicopathological subtype of EBS. What does this study add? We identified a case with new compound heterozygous loss-of-function mutations in EXPH5. The clues to diagnosis came from transmission electron microscopy, with ultrastructural findings of abnormal intracellular vesicles in basal keratinocytes leading to keratin filament aggregation, cytolysis and acantholysis. This study highlights an important and unexpected role for exophilin-5 in maintaining skin integrity.