Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa.

[junctional epidermolysis bullosa]

Junctional epidermolysis bullosa (JEB ), a group of hereditary skin fragility disorders , is associated with a wide variety of phenotypes , although all forms are characterised by trauma induced skin blistering and tissue separation at the dermal-epidermal junction zone . A subgroup , coined JEB -other , is associated with mutations in the COL 17 A 1 gene encoding collagen XVII or , more rarely , with mutations in the laminin 332 genes LAMA 3 , LAMB 3 , or LAMC 2 . The objective of this study is comprehensive genotype-phenotype analysis in JEB -other patients with COL 17 A 1 mutations and elucidation of disease mechanisms underlying different skin phenotypes .COL 17 A 1 mutations and their clinical and cellular consequences were systematically analysed in 43 patients with JEB -other . Cell culture , RT-PCR , and protein biochemistry were applied to assess the effects of splice site mutations -that is , the nature and amounts of transcripts and polypeptides synthesised and their association with the phenotypic outcome . 34 distinct COL 17 A 1 mutations were disclosed , 12 of them novel . mRNA and protein analyses demonstrated that patients with only about 12 -14 % of the physiological collagen XVII levels had mild cutaneous involvement and a long life span .In contrast to complete null phenotypes , presence of minor amounts of collagen XVII protein in JEB skin is associated with mild phenotypic manifestations . The data have significant implications for design of molecular therapies for JEB , since they suggest that already a low extent of collagen XVII restoration will improve skin stability and alleviate symptoms .

Diseases
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Diseases presenting "skin phenotypes" symptom

junctional epidermolysis bullosa

lamellar ichthyosis

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