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 α6β4 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 β4 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 β4 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.
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Abbreviations
- EB-PA:
-
epidermolysis bullosa with pyloric atresia
- BMZ:
-
basement membrane zone
- CSGE:
-
conformation-sensitive gel electrophoresis
- PTC:
-
premature termination codon
- TEM:
-
transmission electron microscopy
- ITGB4:
-
β4 integrin gene
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Acknowledgements
The authors thank the families participating in this study. Dr. J.-D. Fine, National Epidermolysis Bullosa Registry, University of North Carolina, Chapel Hill, assisted in diagnostic evaluation and provided electron microscopy and immunofluorescence service to the patients. Dr. A. Sonnenberg, the Netherlands Cancer Institute, Amsterdam, Netherlands; Dr. K. Owaribe, Nagoya University, Nagoya, Japan; and Dr. P. Marinkovich, Stanford University, Palo Alto, CA, provided the Mab recognizing α6 integrin (GoH3), β4 integrin (3E1), plectin (HD121), and type VII collagen (NP185). Dr. G. Bennett, Canberra Hospital, assisted with the electron micrographs, and D. Bhargava, St George Hospital, Sydney, and C.W. Chow, Royal Children’s Hospital, Melbourne, assisted with antibody staining.
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Supported by the United States Public Health Service, National Institutes of Health Grant PO1 AR 38923.
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Nakano, A., Pulkkinen, L., Murrell, D. et al. Epidermolysis Bullosa with Congenital Pyloric Atresia: Novel Mutations in the β4 Integrin Gene (ITGB4) and Genotype/Phenotype Correlations. Pediatr Res 49, 618–626 (2001). https://doi.org/10.1203/00006450-200105000-00003
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DOI: https://doi.org/10.1203/00006450-200105000-00003
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