Phenotypic spectrum of epidermolysis bullosa associated with α6β4 integrin mutations

• Published in: British journal of dermatology (1951) Vol. 169; no. 1; pp. 115 - 124
• Main Authors: Schumann, H., Kiritsi, D., Pigors, M., Hausser, I., Kohlhase, J., Peters, J., Ott, H., Hyla-Klekot, L., Gacka, E., Sieron, A.L., Valari, M., Bruckner-Tuderman, L., Has, C.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.07.2013; Wiley-Blackwell
• Subjects: Adolescent; Adult; Biological and medical sciences; Bullous diseases of the skin; Child; Child, Preschool; Dermatology; DNA - analysis; Epidermolysis Bullosa - genetics; Epidermolysis Bullosa - pathology; Fatal Outcome; Female; Fluorescent Antibody Technique; Genotype; Humans; Infant; Integrin alpha6beta4 - genetics; Integrin beta4 - genetics; Male; Medical sciences; Microscopy, Electron; Mutation - genetics; Phenotype; Skin - ultrastructure; Bullous dermatosis; Immunopathology; Skin disease; Phenotype; Association; Integrin; Epidermolysis bullosa; Dermatology; Cell adhesion molecule; Autoimmune disease; Mutation
• ISSN: 0007-0963; 1365-2133
• DOI: 10.1111/bjd.12317

Summary Background Integrin α6β4 is a transmembrane receptor and a key component of the hemidesmosome anchoring complex. It is involved in cell–matrix adhesion and signalling in various tissues. Mutations in the ITGA6 and ITGB4 genes coding for α6β4 integrin compromise dermal–epidermal adhesion and are associated with skin blistering and pyloric atresia (PA), a disorder known as epidermolysis bullosa with PA (EB‐PA). Objectives To elucidate the molecular pathology of skin fragility in eight cases, disclose the underlying ITGA6 and ITGB4 mutations and study genotype–phenotype correlations. Methods DNA was isolated from ethylenediaminetetraacetic acid–blood samples, and the coding exons and exon–intron boundaries of ITGA6 and ITGB4 were amplified by polymerase chain reaction (PCR), and directly sequenced. Skin samples were submitted to immunofluorescence mapping with antibodies to adhesion proteins of the dermal–epidermal junction. Primary keratinocytes were isolated, and used for RNA and protein extraction, reverse transcription PCR and immunoblotting. Ultrastructural analysis of the skin was performed in one patient. Results We disclose 10 novel mutations, one in ITGA6 and nine in ITGB4. Skin cleavage was either intraepidermal or junctional. Lethal outcome and PA correlated with loss‐of‐function mutations in two cases. Solely mild skin involvement was associated with deletion of the C‐terminus of β4 integrin. Combinations of missense, nonsense or frameshift mutations caused severe urinary tract involvement in addition to skin fragility in five cases. Conclusions The present study reveals novel ITGA6 and ITGB4 gene mutations and supports previous reports showing that the phenotype may lack PA and be limited to skin and nail involvement. In four out of six cases of EB‐PA, life expectancy was not impaired. A high frequency of urinary tract involvement was found in this study, and represented the main cause of morbidity. Low levels of β4 integrin expression were compatible with hemidesmosomal integrity and a mild skin phenotype. What's already known about this topic? Epidermolysis bullosa (EB) with pyloric atresia (PA) is a rare EB type caused by mutations in the genes coding for α6β4 integrin or plectin, disrupting the hemidesmosome adhesion complex. A reduced life expectancy is predicted in most cases of EB with PA. α6β4 integrin gene mutations are not always associated with PA. What does this study add? This study identifies 10 novel ITGB4 and ITGA6 mutations causing a spectrum of phenotypes, ranging from mild skin blistering to a lethal multisystem disorder with skin, urinary and gastrointestinal involvement. Urinary tract involvement is relatively common (five out of eight cases in this study). Low levels of α6β4 integrin are sufficient for hemidesmosomal integrity and are associated with a mild skin phenotype.