Epidermolysis bullosa with pyloric atresia (
EB-PA: OMIM 226730), also known as
Carmi syndrome, is a rare autosomal recessive genodermatosis that manifests with neonatal mucocutaneous fragility associated with congenital pyloric atresia. The disease is frequently lethal within the first year, but nonlethal cases have been reported. Mutations in the genes encoding subunit
polypeptides of the
alpha 6 beta 4 integrin (ITGA6 and ITGB4) have been demonstrated in
EB-PA patients. To extend the repertoire of mutations and to identify genotype-phenotype correlations, we examined seven new
EB-PA families, four with lethal and three with nonlethal disease variants.
DNA from patients was screened for mutations using heteroduplex analysis followed by
nucleotide sequencing of PCR products spanning all beta 4
integrin-coding sequences. Mutation analysis disclosed 12 distinct mutations, 11 of them novel. Four mutations predicted a
premature termination codon as a result of
nonsense mutations or small out-of-frame insertions or deletions, whereas seven were missense mutations. This brings the total number of distinct ITGB4 mutations to 33. The mutation database indicates that
premature termination codons are associated predominantly with the lethal
EB-PA variants, whereas missense mutations are more prevalent in nonlethal forms. However, the consequences of the missense mutations are position dependent, and substitutions of highly conserved
amino acids may have lethal consequences. In general, indirect immunofluorescence studies of affected skin revealed negative staining for beta 4
integrin in lethal cases and positive, but attenuated, staining in nonlethal cases and correlated with clinical phenotype. The data on specific mutations in
EB-PA patients allows prenatal testing and preimplantation genetic diagnosis in families at risk.