Funding sources This research was supported by DEBRA (U.K.) and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London.
Mutations in EXPH5 result in autosomal recessive inherited skin fragility
Version of Record online: 13 JAN 2014
© 2013 British Association of Dermatologists
British Journal of Dermatology
Volume 170, Issue 1, pages 196–199, January 2014
How to Cite
Liu, L., Mellerio, J.E., Martinez, A.E., McMillan, J.R., Aristodemou, S., Parsons, M. and McGrath, J.A. (2014), Mutations in EXPH5 result in autosomal recessive inherited skin fragility. British Journal of Dermatology, 170: 196–199. doi: 10.1111/bjd.12723
Conflicts of interest None declared.
- Issue online: 13 JAN 2014
- Version of Record online: 13 JAN 2014
- Accepted manuscript online: 6 NOV 2013 12:21PM EST
- Manuscript Accepted: 3 NOV 2013
- National Institute for Health Research (NIHR)
- St Thomas' NHS Foundation Trust
- King's College London
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.Pro649fsPro*11) 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.