title: Epidermolysis bullosa with congenital pyloric atresia: novel mutations in the beta 4 integrin gene (ITGB4) and genotype/phenotype correlations.
abstract: 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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nakano
authors.forename: L
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: D
authors.initials: D
authors.lastname: Murrell
authors.forename: J
authors.initials: J
authors.lastname: Rico
authors.forename: A W
authors.initials: AW
authors.lastname: Lucky
authors.forename: M
authors.initials: M
authors.lastname: Garzon
authors.forename: C A
authors.initials: CA
authors.lastname: Stevens
authors.forename: S
authors.initials: S
authors.lastname: Robertson
authors.forename: E
authors.initials: E
authors.lastname: Pfendner
authors.forename: J
authors.initials: J
authors.lastname: Uitto
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D004820:Epidermolysis Bullosa / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006801:Humans; D039663:Integrin beta4; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011708:Pylorus / Q000002:abnormalities*; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000473:pathology / Q000648:ultrastructure
chemical_list: D015703:Antigens, CD; D017931:DNA Primers; D039663:Integrin beta4