Mutations inEXPH5result in autosomal recessive inherited skin fragility

Abstract

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.

A novel homozygous deletion inEXPH5causes a skin fragility phenotype

“…The disease is usually inherited as an autosomal dominant trait. By contrast, as in this and previous reports, EBS associated with mutations in EXPH5 shows recessive inheritance as well as very mild mechanical skin fragility, along with histopathological findings similar to those reported for other forms of basal EBS (Table ).…”

“…To date, five genes have been implicated as being responsible for the diverse subtypes of basal EBS, including EXPH5 , in which a novel deletion was identified in the present study. Three points support the pathogenicity of this mutation: (i) it cosegregated with the disease phenotype in the family; (ii) it was not found in a large group of healthy controls, suggesting that it does not represent a neutral polymorphism; and (iii) it was predicted to lead to loss of protein expression, as with all the other EXPH5 mutations reported to date as causing EBS …”

“…Most cases of basal EBS are attributable to mutations in the KRT5 and KRT14 genes encoding keratins 5 and 14, while a minority of those cases is due to mutations in the PLEC and DST genes encoding plectin and dystonin, respectively . Recently, mutations in a fifth gene, EXPH5 (encoding exophilin‐5, also known as Slac2‐b) were shown to cause a recessive form of basal EBS …”

Mutations in EXPH5 underlie a rare subtype of autosomal recessive epidermolysis bullosa simplex

“…There are only three previous reports (five cases) of EXPH5 mutations in kindreds with a similar, mild skin fragility phenotype . One of the five previously reported cases had extensive erosions at birth; the other four had normal skin at birth.…”

“…The first pedigree of autosomal recessive EBS with mutations in EXPH5 was diagnosed following whole‐exome sequencing; the second was identified by screening a cohort of undiagnosed cases of EBS for which screening of previously known candidate genes had been negative; the third was established after ultrastructural findings of abnormal cytoplasmic vesicles . In contrast, our fourth pedigree was diagnosed clinically.…”