Deletion of a Cytoplasmic Domain of Integrin β4 Causes Epidermolysis Bullosa Simplex1
| Autor: | Marcel F. Jonkman, Hendri H. Pas, Gerrit van der Steege, Miranda Nijenhuis, GJ Kloosterhuis |
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| Rok vydání: | 2002 |
| Předmět: |
collagen
Integrin beta4 Hemidesmosome Integrin Plectin Cell Biology Dermatology Biology medicine.disease basement membrane Virology Molecular biology Null allele Biochemistry bullous disease Fibronectin Epidermolysis bullosa simplex medicine biology.protein hemidesmosome Epidermolysis bullosa Molecular Biology |
| Zdroj: | Journal of Investigative Dermatology. 119(6):1275-1281 |
| ISSN: | 0022-202X |
| DOI: | 10.1046/j.1523-1747.2002.19609.x |
| Popis: | Integrin α6β4 is a hemidesmosomal transmembrane molecule involved in maintaining basal cell-matrix adhesion through interaction of the large intracytoplasmic tail of the β4 subunit with the keratin intermediate filament network, at least in part through its binding with plectin and BP180/type XVII collagen. Here we report a patient with predominant features of epidermolysis bullosa simplex due to a mutation in the integrin β4 gene. The patient, a 49-y-old female, had mild blistering of hands and feet from birth on, dystrophy of the nails with onychogryposis, and enamel hypoplasia. She had no alopecia and no history of pyloric atresia. Electron microscopy and antigen mapping of a skin blister revealed that the level of separation was intraepidermal, low in the basal keratinocytes through the attachment plaque of the hemidesmosome. Immuno-fluorescence microscopy revealed absent binding of monoclonal antibody 450–11 A against the third fibronectin III repeat on the intracellular domain of integrin β4, whereas binding was reduced with monoclonal antibodies recognizing epitopes on amino-terminal and carboxy-terminal ends of the polypeptide. At the molecular level the phenotype was caused by a novel 2 bp deletion 4733delCT in ITGB4 , resulting in in-frame skipping of exon 36 and a deduced 50 amino acid deletion (1450–1499) within the third fibronectin type III repeat in the cytoplasmic domain of the integrin β4 polypeptide. Immunoblot analysis demonstrated a 5 kDa shorter β4 polypeptide. The 4733delCT mutation was heterozygously present in the DNA. The patient is also expected to be heterozygous for a null allele, as no full-size protein was detected in vitro and the epitope 450–11 A was absent in vivo . These data show that deletion of the third fibronectin type III repeat in the cytoplasmic domain of integrin β4, which is thought to interact with BP180/type XVII collagen, is clinically pathogenic and results in a mild phenotype with predominant features of epidermolysis bullosa simplex. |
| Databáze: | OpenAIRE |
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