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.

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Isodicentric 17q is the most commonly reported chromosomal abnormality in medulloblastomas. Its frequency suggests that genes disrupted in medulloblastoma formation may play a role in tumorigenesis. We have previously identified two chromosome 17 breakpoint at a 1 Mb resolution. Our aims were to accurately map the position of these breakpoints and to identify mechanisms of gene disruption at this site. CGH with a custom tiling path genomic BAC array of chromosome 17 enriched with fosmids at the breakpoint regions was used to analyze a series of 45 medulloblastomas and three medulloblastoma-derived cell lines. In total, 17 of 45 medulloblastomas had an isodicentric 17q. Two breakpoint regions were identified and their positions were mapped. The array identified a more complex arrangement at the breakpoint than has been reported previously using lower resolution BAC arrays. The patterns observed indicated that dicentric chromosome formation occurs both via nonallelic homologous recombination between palindromically arranged low copy repeats (the previously accepted mechanism) and by recombination between nonidentical sequences. In addition, novel alternative structural alterations, a homozygous deletion and a duplication, were identified within the chromosome breakpoint region in two cases. At the resolution of the array, these structural alterations spanned the same genes as cases with dicentric 17q formation, implying that the disruption of genes at the chromosome breakpoint itself may be of greater biological significance than has previously been suspected.

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