title: Association of Epidermolysis Bullosa Simplex With Mottled Pigmentation and EXPH5 Mutations.
abstract: Epidermolysis bullosa simplex (EBS) is a group of clinically and genetically diverse mechanobullous genodermatoses characterized by the fragility of skin and mucous membranes. Recently, mutations in EXPH5 encoding exophilin-5 (also known as Slac2-b, an effector protein involved in intracellular vesicle trafficking and exosome secretion) have been implicated in the pathophysiology of EBS. Herein, we report a novel homozygous nonsense mutation in EXPH5 responsible for an EBS subtype with mottled pigmentation.
  
  
  
  To identify the gene mutation(s) accountable for the mottled pigmentation phenotype in a patient with suspected inherited skin fragility disorder.
  
  
  
  Data for this case report were acquired in an outpatient clinic and concern a referral from the primary care physician to the national Center for Blistering Diseases in The Netherlands. Data were acquired and analyzed from 2014 to 2016.
  
  
  
  Clinical examination and investigation were performed of the molecular basis of patient's skin fragility and mottled pigmentation phenotype. Electron microscopy studies described the underlying abnormalities on an ultrastructural level.
  
  
  
  The clinical phenotype is characterized by mild generalized skin fragility, trauma-induced skin blistering since infancy, and development of remarkable diffuse mottled pigmentation on the trunk and proximal extremities. Sequencing the complete set of genes associated with epidermolysis bullosa revealed a homozygous nonsense mutation in exon 6 of EXPH5: c.3917C>G, p.Ser1306*. Electron microscopy revealed disruption of keratin filament cytoskeleton and accumulation of melanosomes in a disordered distribution in the keratinocytes.
  
  
  
  To our knowledge, the current study illustrates the first clinically well-documented, mottled pigmentation phenotype related to a novel EXPH5 mutation. In addition, by means of electron microscopy image analysis, it proposes a hypothesis for the pigmentary changes in this rare autosomal recessive EBS subtype. These findings expand the genetic and phenotypic spectrum of human inherited skin fragility disorders, and we propose the addition of EBS resulting from EXPH5 mutations to the EBS-mottled pigmentation subtype.
authors.affiliation: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Iana
authors.initials: I
authors.lastname: Turcan
authors.affiliation: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Anna M G
authors.initials: AM
authors.lastname: Pasmooij
authors.affiliation: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands2Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Van den Akker
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Henny
authors.initials: H
authors.lastname: Lemmink
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sinke
authors.affiliation: Center for Blistering Diseases, Department of Dermatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Marcel F
authors.initials: MF
authors.lastname: Jonkman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D015415:Biomarkers / Q000097:blood; D018389:Codon, Nonsense / Q000235:genetics*; D003241:Consanguinity; D016110:Epidermolysis Bullosa Simplex / Q000175:diagnosis* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D010641:Phenotype; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D018389:Codon, Nonsense; C514892:EXPH5 protein, human