Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia.

Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a rare congenital bullous disease with gastrointestinal disturbance that has been associated with mutations in ITGA6 or ITGB4 encoding the α6 or β4 subunit of integrin, respectively. Only six ITGA6 mutations in PA-JEB have been reported while many ITGB4 mutations have been identified, and all the ITGA6 mutations were homozygous. Here, we report a case of lethal type PA-JEB, in which immunofluorescence showed the lack of both α6 and β4 integrins resulting from compound heterozygous splice site mutation in ITGA6, c.387G>T and c.2506-1G>C. Maternal c.387G>T induced the skipping of the entire exon 3 and both exons 3 and 4, resulting in premature termination codon and in-frame deletion, respectively. Paternal c.2506-1G>C caused the skipping of the exon 20 and resulted in in-frame deletion. As a reason why the present case showed lethal phenotype despite the in-frame deletion mutation, rapid degradation of neo-synthesized α6 protein and/or impaired transport of integrin were suggested from previous reports, and the lack of localization of integrin α6β4 to the epidermal basement membrane resulted in skin fragility. Our case expands the variety of integrin α6 mutations in PA-JEB.