Molecular Heterogeneity of Epidermolysis Bullosa Simplex: Contribution of EXPH5 Mutations

Pigors, Manuela; Schwieger‐Briel, Agnes; Leppert, Juna; Kiritsi, Dimitra; Kohlhase, Jürgen; Bruckner‐Tuderman, Leena; Has, Cristina

doi:10.1038/jid.2013.373

Cited by 20 publications

(32 citation statements)

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“…Recently, we reported a further new subtype of autosomal recessive EBS caused by a homozygous frameshift mutation in the EXPH5 gene, which encodes exophilin‐5 (Slac2‐b), an effector protein of the Rab GTPase Rab27B, which has a role in intracellular vesicle trafficking . Subsequently, a second pedigree with compound heterozygous frameshift mutations in EXPH5 was also reported . Here, we describe a third example of inherited skin fragility resulting from a nonsense/frameshift combination of mutations in EXPH5 that provides further insight into the role of exophilin‐5 in keratinocyte cell biology and human blistering skin diseases.…”

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confidence: 80%

Mutations inEXPH5result in autosomal recessive inherited skin fragility

et al. 2014

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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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Mutations inEXPH5result in autosomal recessive inherited skin fragility

et al. 2014

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“…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.…”

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

et al. 2015

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“…EXPH5 mutations leading to premature termination codons and absence of Slac2b seem to represent are a rare cause of EB simplex. Clinical manifestations are usually mild, and skin fragility improves with age (Figure B,C). Remarkable mottled pigmentation was reported in a single case …”

Section: New Eb Clinical Phenotypesmentioning

confidence: 87%

Inherited epidermolysis bullosa: New diagnostics and new clinical phenotypes

Has

Fischer

2018

Experimental Dermatology

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Inherited epidermolysis bullosa (EB) is a group of heterogeneous genetic disorders characterized by skin fragility. EB comprises a large spectrum of phenotypes, ranging from severe cutaneous and extracutaneous involvement caused by lack of key adhesion proteins, to mild cutaneous fragility caused by subtle molecular defects. Disease-causing variants in 20 different genes account for the genetic and allelic heterogeneity of EB. Here, we discuss the development of laboratory methods that enabled these discoveries and the clinical and molecular features of some new EB entities elucidated during the past 5-6 years.

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Molecular Heterogeneity of Epidermolysis Bullosa Simplex: Contribution of EXPH5 Mutations

Cited by 20 publications

References 12 publications

Mutations inEXPH5result in autosomal recessive inherited skin fragility

Mutations inEXPH5result in autosomal recessive inherited skin fragility

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

Inherited epidermolysis bullosa: New diagnostics and new clinical phenotypes

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