title: Compound heterozygosity for missense (L156P) and nonsense (R554X) mutations in the beta4 integrin gene (ITGB4) underlies mild, nonlethal phenotype of epidermolysis bullosa with pyloric atresia.
abstract: Mutations in the genes encoding the subunit polypeptides of the alpha6beta4 integrin (ITGA6 and ITGB4, respectively) have been previously demonstrated in patients with a lethal form of epidermolysis bullosa with congenital pyloric atresia (OMIM #226730). In this study, we demonstrate for the first time ITGB4 mutations in nonlethal phenotype of epidermolysis bullosa with congenital pyloric atresia. Specifically, the proband was shown to be a compound heterozygote for a missense mutation (L156P) and a nonsense mutation (R554X). The leucine substitution by proline was shown to affect a residue, which was precisely conserved in different human, rodent, and drosophila integrin-beta polypeptides, and consequently disrupts the alpha-helix formation of the polypeptide segment as determined by Garnier alpha-helicity plot. The nonsense mutation in another allele was accompanied by undetectable levels of the corresponding mRNA transcript, as determined by reverse transcription-polymerase chain reaction. The presence of a missense mutation, when combined with a premature termination codon mutation, may explain the milder blistering tendency of the skin in this patient.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Philadelphia, Pennsylvania 19107, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: L
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.forename: C
authors.initials: C
authors.lastname: August
authors.forename: J
authors.initials: J
authors.lastname: Uitto
mesh_terms: D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics*; D015153:Blotting, Western; D004820:Epidermolysis Bullosa / Q000150:complications / Q000235:genetics* / Q000473:pathology; D019084:Fluorescent Antibody Technique, Indirect; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D039663:Integrin beta4; D016023:Integrins / Q000235:genetics; D007409:Intestinal Atresia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011708:Pylorus / Q000002:abnormalities*; D014158:Transcription, Genetic
chemical_list: D015703:Antigens, CD; D039663:Integrin beta4; D016023:Integrins