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Hiroshi Shimizu - One of the best experts on this subject based on the ideXlab platform.
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plectin deficiency leads to both muscular dystrophy and Pyloric Atresia in epidermolysis bullosa simplex
Human Mutation, 2010Co-Authors: Ken Natsuga, Makiko Ohyama, Takeshi Kambara, Hitoshi Osaka, Ken Arita, Hideki Nakamura, Yoshiaki Hirako, Wataru Nishie, Satoru Shinkuma, Hiroshi ShimizuAbstract:Plectin is a cytoskeletal linker protein which has a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC) cause two distinct autosomal recessive subtypes of epidermolysis bullosa: EB simplex (EBS) with muscular dystrophy (EBS-MD), and EBS with Pyloric Atresia (EBS-PA). Previous studies have demonstrated that loss of full-length plectin with residual expression of the rodless isoform leads to EBS-MD, whereas complete loss or marked attenuation of expression of full-length and rodless plectin underlies the more severe EBS-PA phenotype. However, muscular dystrophy has never been identified in EBS-PA, not even in the severe form of the disease. Here, we report the first case of EBS associated with both Pyloric Atresia and muscular dystrophy. Both of the premature termination codon-causing mutations of the proband are located within exon 32, the last exon of PLEC. Immunofluorescence and immunoblot analysis of skin samples and cultured fibroblasts from the proband revealed truncated plectin protein expression in low amounts. This study demonstrates that plectin deficiency can indeed lead to both muscular dystrophy and Pyloric Atresia in an individual EBS patient. © 2010 Wiley-Liss, Inc.
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Pyloric Atresia-junctional epidermolysis bullosa syndrome showing novel 594insC/Q425P mutations in integrin beta4 gene (ITGB4).
Experimental dermatology, 2004Co-Authors: Takuji Masunaga, Takeji Nishikawa, Akira Ishiko, Yasuko Takizawa, Soo-chan Kim, Jin Sung Lee, Hiroshi ShimizuAbstract:Pyloric Atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is an autosomal recessive inherited rare blistering disorder caused by mutations in ITGA6 or ITGB4, genes encoding integrin alpha6 or beta4, respectively. In this study, we have disclosed the mutations in ITGB4 in a Korean patient with PA-JEB. The proband, who showed skin blisters, was diagnosed as having Pyloric Atresia and died 2 years after birth. Mutational analysis showed a novel 594insC maternal mutation in exon 7, which led to premature termination codon (PTC), and a novel Q425P paternal mutation in exon 11. Q425P mutation was not detected in 200 alleles obtained from a normal healthy Korean control, and was shown to reduce alpha-helix forming ability in integrin beta4 a by Garnier alpha-helicity plot of the protein, indicating that this mutation is pathogenic but not polymorphism. The phenotype in the present case can be explained by (1) the combination of PTC and missense mutation, and (2) amino-acid substitution occurring for the amino acid not preserved in the integrin beta family. Our results contribute to further the accumulation of mutation data for better understanding of the genotype/phenotype correlation in PA-JEB, and may give profound insight into the role of integrins alpha6 and beta4.
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Pyloric Atresia junctional epidermolysis bullosa syndrome showing novel 594insc q425p mutations in integrin beta4 gene itgb4
Experimental Dermatology, 2004Co-Authors: Takuji Masunaga, Takeji Nishikawa, Akira Ishiko, Yasuko Takizawa, Soo-chan Kim, Jin Sung Lee, Hiroshi ShimizuAbstract:Pyloric Atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is an autosomal recessive inherited rare blistering disorder caused by mutations in ITGA6 or ITGB4, genes encoding integrin alpha6 or beta4, respectively. In this study, we have disclosed the mutations in ITGB4 in a Korean patient with PA-JEB. The proband, who showed skin blisters, was diagnosed as having Pyloric Atresia and died 2 years after birth. Mutational analysis showed a novel 594insC maternal mutation in exon 7, which led to premature termination codon (PTC), and a novel Q425P paternal mutation in exon 11. Q425P mutation was not detected in 200 alleles obtained from a normal healthy Korean control, and was shown to reduce alpha-helix forming ability in integrin beta4 a by Garnier alpha-helicity plot of the protein, indicating that this mutation is pathogenic but not polymorphism. The phenotype in the present case can be explained by (1) the combination of PTC and missense mutation, and (2) amino-acid substitution occurring for the amino acid not preserved in the integrin beta family. Our results contribute to further the accumulation of mutation data for better understanding of the genotype/phenotype correlation in PA-JEB, and may give profound insight into the role of integrins alpha6 and beta4.
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Absence of Detectable a6 Integrin in Pyloric Atresia-Junctional Epidermolysis Bullosa Syndrome: Application for Prenatal Diagnosis in a Family at Risk for Recurrence
Archives of dermatology, 1996Co-Authors: Hiroshi Shimizu, Kaoru Suzumori, Naohito Hatta, Takeji NishikawaAbstract:Background and Design: The expression of basement membrane—related antigens was surveyed in 2 Japanese siblings who died of Pyloric Atresia—junctional epidermolysis bullosa syndrome in early infancy. Results: The skin specimens of both patients demonstrated complete absence of detectable α 6 integrin and markedly reduced amounts of β 4 integrin. All the other subtypes of epidermolysis bullosa used as controls demonstrated normal intensity of expression of α 6 and β 4 integrin. In contrast to the negative immunoreactivity of monoclonal antibody GB3 in gravis-Herlitz junctional epidermolysis bullosa (n=4), a bright linear pattern along the epidermal basement membrane was demonstrated in the skin of both siblings with Pyloric Atresia—junctional epidermolysis bullosa syndrome. Based on these data, a monoclonal antibody against α 6 integrin was successfully used as a prenatal diagnostic probe for a skin biopsy specimen from a fetus at risk for Pyloric Atresia— junctional epidermolysis bullosa syndrome in this family. Conclusion: The absence of detectable α 6 integrin, but not β 4 integrin, in these cases raises the possibility that α6 integrin or its ligands are responsible for the Pyloric Atresia—junctional epidermolysis bullosa syndrome phenotype seen in this family. Arch Dermatol. 1996;132:919-925
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Prenatal exclusion of Pyloric Atresia-junctional epidermolysis bullosa syndrome
Journal of the American Academy of Dermatology, 1994Co-Authors: Hiroshi Shimizu, Kaoru Suzumori, Naohito Hatta, Jo-david Fine, Makio Shozu, Takeji NishikawaAbstract:Background: The Pyloric Atresia—junctional epidermolysis bullosa (PA-JEB) syndrome is an autosomal recessive disorder with a poor prognosis. Electron microscopy of fetal skin has been the only reliable method for prenatal diagnosis. Objective: The purpose of this study was to make the prenatal diagnosis of PA-JEB syndrome with a more reliable method by means of immunocytochemical probes. Methods: Expression of a range of basement membrane antigens was examined in different types of JEB. On the basis of the results, a fetal skin biopsy specimen was obtained for prenatal diagnosis. Results: In PA-JEB syndrome (n = 2), GB3 antigen (BM600) was normally expressed; the 19-DEJ-1 antigen was completely absent. In fetal skin at risk for PA-JEB syndrome, the 19-DEJ-1 antigen was normally expressed, and no ultrastructural abnormality was found by electron microscopy. A normal male infant was delivered at 38 weeks of pregnancy. Conclusion: 19-DEJ-1 monoclonal antibody serves as a useful probe for the prenatal diagnosis of PA-JEB syndrome.
Takeji Nishikawa - One of the best experts on this subject based on the ideXlab platform.
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Pyloric Atresia junctional epidermolysis bullosa syndrome showing novel 594insc q425p mutations in integrin beta4 gene itgb4
Experimental Dermatology, 2004Co-Authors: Takuji Masunaga, Takeji Nishikawa, Akira Ishiko, Yasuko Takizawa, Soo-chan Kim, Jin Sung Lee, Hiroshi ShimizuAbstract:Pyloric Atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is an autosomal recessive inherited rare blistering disorder caused by mutations in ITGA6 or ITGB4, genes encoding integrin alpha6 or beta4, respectively. In this study, we have disclosed the mutations in ITGB4 in a Korean patient with PA-JEB. The proband, who showed skin blisters, was diagnosed as having Pyloric Atresia and died 2 years after birth. Mutational analysis showed a novel 594insC maternal mutation in exon 7, which led to premature termination codon (PTC), and a novel Q425P paternal mutation in exon 11. Q425P mutation was not detected in 200 alleles obtained from a normal healthy Korean control, and was shown to reduce alpha-helix forming ability in integrin beta4 a by Garnier alpha-helicity plot of the protein, indicating that this mutation is pathogenic but not polymorphism. The phenotype in the present case can be explained by (1) the combination of PTC and missense mutation, and (2) amino-acid substitution occurring for the amino acid not preserved in the integrin beta family. Our results contribute to further the accumulation of mutation data for better understanding of the genotype/phenotype correlation in PA-JEB, and may give profound insight into the role of integrins alpha6 and beta4.
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Pyloric Atresia-junctional epidermolysis bullosa syndrome showing novel 594insC/Q425P mutations in integrin beta4 gene (ITGB4).
Experimental dermatology, 2004Co-Authors: Takuji Masunaga, Takeji Nishikawa, Akira Ishiko, Yasuko Takizawa, Soo-chan Kim, Jin Sung Lee, Hiroshi ShimizuAbstract:Pyloric Atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is an autosomal recessive inherited rare blistering disorder caused by mutations in ITGA6 or ITGB4, genes encoding integrin alpha6 or beta4, respectively. In this study, we have disclosed the mutations in ITGB4 in a Korean patient with PA-JEB. The proband, who showed skin blisters, was diagnosed as having Pyloric Atresia and died 2 years after birth. Mutational analysis showed a novel 594insC maternal mutation in exon 7, which led to premature termination codon (PTC), and a novel Q425P paternal mutation in exon 11. Q425P mutation was not detected in 200 alleles obtained from a normal healthy Korean control, and was shown to reduce alpha-helix forming ability in integrin beta4 a by Garnier alpha-helicity plot of the protein, indicating that this mutation is pathogenic but not polymorphism. The phenotype in the present case can be explained by (1) the combination of PTC and missense mutation, and (2) amino-acid substitution occurring for the amino acid not preserved in the integrin beta family. Our results contribute to further the accumulation of mutation data for better understanding of the genotype/phenotype correlation in PA-JEB, and may give profound insight into the role of integrins alpha6 and beta4.
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Absence of Detectable a6 Integrin in Pyloric Atresia-Junctional Epidermolysis Bullosa Syndrome: Application for Prenatal Diagnosis in a Family at Risk for Recurrence
Archives of dermatology, 1996Co-Authors: Hiroshi Shimizu, Kaoru Suzumori, Naohito Hatta, Takeji NishikawaAbstract:Background and Design: The expression of basement membrane—related antigens was surveyed in 2 Japanese siblings who died of Pyloric Atresia—junctional epidermolysis bullosa syndrome in early infancy. Results: The skin specimens of both patients demonstrated complete absence of detectable α 6 integrin and markedly reduced amounts of β 4 integrin. All the other subtypes of epidermolysis bullosa used as controls demonstrated normal intensity of expression of α 6 and β 4 integrin. In contrast to the negative immunoreactivity of monoclonal antibody GB3 in gravis-Herlitz junctional epidermolysis bullosa (n=4), a bright linear pattern along the epidermal basement membrane was demonstrated in the skin of both siblings with Pyloric Atresia—junctional epidermolysis bullosa syndrome. Based on these data, a monoclonal antibody against α 6 integrin was successfully used as a prenatal diagnostic probe for a skin biopsy specimen from a fetus at risk for Pyloric Atresia— junctional epidermolysis bullosa syndrome in this family. Conclusion: The absence of detectable α 6 integrin, but not β 4 integrin, in these cases raises the possibility that α6 integrin or its ligands are responsible for the Pyloric Atresia—junctional epidermolysis bullosa syndrome phenotype seen in this family. Arch Dermatol. 1996;132:919-925
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Prenatal exclusion of Pyloric Atresia-junctional epidermolysis bullosa syndrome
Journal of the American Academy of Dermatology, 1994Co-Authors: Hiroshi Shimizu, Kaoru Suzumori, Naohito Hatta, Jo-david Fine, Makio Shozu, Takeji NishikawaAbstract:Background: The Pyloric Atresia—junctional epidermolysis bullosa (PA-JEB) syndrome is an autosomal recessive disorder with a poor prognosis. Electron microscopy of fetal skin has been the only reliable method for prenatal diagnosis. Objective: The purpose of this study was to make the prenatal diagnosis of PA-JEB syndrome with a more reliable method by means of immunocytochemical probes. Methods: Expression of a range of basement membrane antigens was examined in different types of JEB. On the basis of the results, a fetal skin biopsy specimen was obtained for prenatal diagnosis. Results: In PA-JEB syndrome (n = 2), GB3 antigen (BM600) was normally expressed; the 19-DEJ-1 antigen was completely absent. In fetal skin at risk for PA-JEB syndrome, the 19-DEJ-1 antigen was normally expressed, and no ultrastructural abnormality was found by electron microscopy. A normal male infant was delivered at 38 weeks of pregnancy. Conclusion: 19-DEJ-1 monoclonal antibody serves as a useful probe for the prenatal diagnosis of PA-JEB syndrome.
J Luan - One of the best experts on this subject based on the ideXlab platform.
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Junctional epidermolysis bullosa associated with congenital localized absence of skin, and Pyloric Atresia in two newborn siblings.
Journal of the American Academy of Dermatology, 2001Co-Authors: S Puvabanditsin, E Garrow, D U Kim, P Tirakitsoontorn, J LuanAbstract:Congenital localized absence of the skin has been observed in various subsets of inherited epidermolysis bullosa (EB). Pyloric Atresia is a rare disorder that has been seen in association with EB. Ureterovesical junction obstruction is a condition unique to the association between Pyloric Atresia and EB. The authors describe 2 premature male siblings with Pyloric Atresia, congenital localized absence of the skin, urinary obstruction, and EB at birth. Electron microscopic study of the biopsy specimen from the first sibling revealed characteristic findings of EB simplex. However, prenatal diagnosis of the next sibling was made by integrin B4 mutations and the electron microscopic study of the biopsy specimen after delivery confirmed junctional EB (JEB). These cases emphasize this unusual combination of defects and limitations of electron microscopy.
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Junctional epidermolysis bullosa associated with congenital localized absence of skin, and Pyloric Atresia in two newborn siblings.
Journal of the American Academy of Dermatology, 2001Co-Authors: S Puvabanditsin, E Garrow, D U Kim, P Tirakitsoontorn, J LuanAbstract:Abstract Congenital localized absence of the skin has been observed in various subsets of inherited epidermolysis bullosa (EB). Pyloric Atresia is a rare disorder that has been seen in association with EB. Ureterovesical junction obstruction is a condition unique to the association between Pyloric Atresia and EB. The authors describe 2 premature male siblings with Pyloric Atresia, congenital localized absence of the skin, urinary obstruction, and EB at birth. Electron microscopic study of the biopsy specimen from the first sibling revealed characteristic findings of EB simplex. However, prenatal diagnosis of the next sibling was made by integrin B4 mutations and the electron microscopic study of the biopsy specimen after delivery confirmed junctional EB (JEB). These cases emphasize this unusual combination of defects and limitations of electron microscopy. (J Am Acad Dermatol 2001;44:330-5.)
Jouni Uitto - One of the best experts on this subject based on the ideXlab platform.
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Epidermolysis bullosa with Pyloric Atresia.
Dermatologic clinics, 2010Co-Authors: Hye Jin Chung, Jouni UittoAbstract:Epidermolysis bullosa (EB) with Pyloric Atresia (PA) is a rare form of EB. This article describes the clinical and pathologic features and molecular genetics of EB-PA, the mutations in the alpha(6)beta(4) integrin and plectin genes that cause EB-PA, and the clinical implications of molecular genetics on EB-PA.
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plectin gene mutations can cause epidermolysis bullosa with Pyloric Atresia
Journal of Investigative Dermatology, 2005Co-Authors: Ellen Pfendner, Jouni UittoAbstract:Epidermolysis bullosa with Pyloric Atresia (EB-PA), manifesting with neonatal blistering and gastric anomalies, is known to be caused by mutations in the hemidesmosomal genes ITGA6 and ITGB4, which encode the α6 and β4 integrin polypeptides, respectively. As part of our molecular diagnostics program, we have now encountered four families with EB-PA in which no mutations could be identified in these two genes. Instead, PCR amplification followed by heteroduplex scanning and/or direct nucleotide sequencing revealed homozygous mutations in the plectin gene (PLEC1), encoding another hemidesmosomal protein previously linked to EB with muscular dystrophy. Our findings provide evidence for additional molecular heterogeneity in EB, and emphasize the importance of screening EB-PA patients not only for α6β4 integrin but also for plectin deficiency.
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Plectin Gene Mutations Can Cause Epidermolysis Bullosa with Pyloric Atresia
The Journal of investigative dermatology, 2005Co-Authors: Ellen Pfendner, Jouni UittoAbstract:Epidermolysis bullosa with Pyloric Atresia (EB-PA), manifesting with neonatal blistering and gastric anomalies, is known to be caused by mutations in the hemidesmosomal genes ITGA6 and ITGB4, which encode the α6 and β4 integrin polypeptides, respectively. As part of our molecular diagnostics program, we have now encountered four families with EB-PA in which no mutations could be identified in these two genes. Instead, PCR amplification followed by heteroduplex scanning and/or direct nucleotide sequencing revealed homozygous mutations in the plectin gene (PLEC1), encoding another hemidesmosomal protein previously linked to EB with muscular dystrophy. Our findings provide evidence for additional molecular heterogeneity in EB, and emphasize the importance of screening EB-PA patients not only for α6β4 integrin but also for plectin deficiency.
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Novel ITGB4 Mutations in Lethal and Nonlethal Variants of Epidermolysis Bullosa with Pyloric Atresia: Missense versus Nonsense
American journal of human genetics, 1998Co-Authors: Leena Pulkkinen, Lynne T. Smith, Tod A. Brown, Fatima Rouan, Leena Bruckner-tuderman, Robert Wallerstein, Maria C. Garzon, William B. Carter, Jouni UittoAbstract:Summary Epidermolysis bullosa with Pyloric Atresia (EB-PA), an autosomal recessive genodermatosis, manifests with neonatal cutaneous blistering associated with congenital Pyloric Atresia. The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the α6β4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants. In this study, we have examined the molecular basis of EB-PA in five families, two of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB-PA was a compound heterozygote for premature termination–codon mutations (C738X/4791delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue (C61Y). The three nonlethal cases had missense mutations in both alleles (C562R/C562R, R1281W/R252C, and R1281W/R1281W). Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for α6 and β4 integrins. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.
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integrin β4 mutations associated with junctional epidermolysis bullosa with Pyloric Atresia
Nature Genetics, 1995Co-Authors: Frederique Vidal, Jouni Uitto, Daniel Aberdam, Corinne Miquel, Angela M Christiano, Leena Pulkkinen, Jeanpaul Ortonne, Guerrino MeneguzziAbstract:Pyloric Atresia associated with junctional epidermolysis bullosa (PA–JEB), is a rare inherited disorder characterized by Pyloric stenosis and blistering of the skin as primary manifestations. We demonstrate that in one PA–JEB patient the disease resulted from two distinct mutations in the β4 integrin gene alleles. The paternal mutation consists of a one base pair deletion causing a shift in the open reading frame, and a downstream premature termination codon. The maternal mutation occurs in a donor splice site, and results in in–frame exon skipping involving the cytoplasmic domain of the polypeptide. Our results implicate mutations in the β4 integrin gene in some forms of PA–JEB.
Naohito Hatta - One of the best experts on this subject based on the ideXlab platform.
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Absence of Detectable a6 Integrin in Pyloric Atresia-Junctional Epidermolysis Bullosa Syndrome: Application for Prenatal Diagnosis in a Family at Risk for Recurrence
Archives of dermatology, 1996Co-Authors: Hiroshi Shimizu, Kaoru Suzumori, Naohito Hatta, Takeji NishikawaAbstract:Background and Design: The expression of basement membrane—related antigens was surveyed in 2 Japanese siblings who died of Pyloric Atresia—junctional epidermolysis bullosa syndrome in early infancy. Results: The skin specimens of both patients demonstrated complete absence of detectable α 6 integrin and markedly reduced amounts of β 4 integrin. All the other subtypes of epidermolysis bullosa used as controls demonstrated normal intensity of expression of α 6 and β 4 integrin. In contrast to the negative immunoreactivity of monoclonal antibody GB3 in gravis-Herlitz junctional epidermolysis bullosa (n=4), a bright linear pattern along the epidermal basement membrane was demonstrated in the skin of both siblings with Pyloric Atresia—junctional epidermolysis bullosa syndrome. Based on these data, a monoclonal antibody against α 6 integrin was successfully used as a prenatal diagnostic probe for a skin biopsy specimen from a fetus at risk for Pyloric Atresia— junctional epidermolysis bullosa syndrome in this family. Conclusion: The absence of detectable α 6 integrin, but not β 4 integrin, in these cases raises the possibility that α6 integrin or its ligands are responsible for the Pyloric Atresia—junctional epidermolysis bullosa syndrome phenotype seen in this family. Arch Dermatol. 1996;132:919-925
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Prenatal exclusion of Pyloric Atresia-junctional epidermolysis bullosa syndrome
Journal of the American Academy of Dermatology, 1994Co-Authors: Hiroshi Shimizu, Kaoru Suzumori, Naohito Hatta, Jo-david Fine, Makio Shozu, Takeji NishikawaAbstract:Background: The Pyloric Atresia—junctional epidermolysis bullosa (PA-JEB) syndrome is an autosomal recessive disorder with a poor prognosis. Electron microscopy of fetal skin has been the only reliable method for prenatal diagnosis. Objective: The purpose of this study was to make the prenatal diagnosis of PA-JEB syndrome with a more reliable method by means of immunocytochemical probes. Methods: Expression of a range of basement membrane antigens was examined in different types of JEB. On the basis of the results, a fetal skin biopsy specimen was obtained for prenatal diagnosis. Results: In PA-JEB syndrome (n = 2), GB3 antigen (BM600) was normally expressed; the 19-DEJ-1 antigen was completely absent. In fetal skin at risk for PA-JEB syndrome, the 19-DEJ-1 antigen was normally expressed, and no ultrastructural abnormality was found by electron microscopy. A normal male infant was delivered at 38 weeks of pregnancy. Conclusion: 19-DEJ-1 monoclonal antibody serves as a useful probe for the prenatal diagnosis of PA-JEB syndrome.
