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- Title
Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease.
- Authors
Mühle, Christiane; Qiu-Jie Jiang; Charlesworth, Alexandra; Bruckner-Tuderman, Leena; Meneguzzi, Guerrino; Schneider, Holm
- Abstract
Herlitz disease (H-JEB), the lethal form of junctional epidermolysis bullosa, is a rare genodermatosis presenting from birth with widespread erosions and blistering of skin and mucosae because of tissue cleavage within the epidermal basement membrane. Mutations in any of the three genes encoding the a3, ß3 and ?2 chains of laminin-5 underlie this recessively inherited disorder. Here, we report the molecular basis and clinical course of H-JEB in 12 patients. Two novel nonsense mutations in the geneLAMA3(E281X and K1299X) and a novel frame-shift mutation in the geneLAMB3(1628insG) leading to a premature termination codon were identified by DNA sequencing and confirmed by restriction fragment length polymorphism analysis. In the four patients affected, neither the resulting truncated polypeptide chains nor assembled laminin-5 protein were detectable by immunofluorescence. Three patients were found to be heterozygous for the known hotspot mutation R635X and the recurrent mutations Q373X or 29insC in the geneLAMB3, whereas five others were homozygous for R635X. Significant variations in the disease progression and survival times between 1 and 30 months in this group of H-JEB patients emphasised the impact of modifying factors and the importance of immunostaining or mRNA assessment as parallel diagnostic methods. Interestingly, the only patients who survived for longer than 6 months were four females carrying the mutation R635X homozygously. In one of them, the clinical course may have been improved by treatment with artificial skin equivalents. These data may stimulate further investigation of genotype-phenotype correlations and facilitate mutation analysis and genetic counselling of affected families.
- Subjects
SKIN diseases; GENETIC mutation; EPIDERMOLYSIS bullosa; GENETIC polymorphisms; HUMAN genetics
- Publication
Human Genetics, 2005, Vol 116, Issue 1/2, p33
- ISSN
0340-6717
- Publication type
Article
- DOI
10.1007/s00439-004-1210-y