Splicing abnormality of integrin β4 gene (ITGB4) due to nucleotide substitutions far from splice site underlies pyloric atresia-junctional epidermolysis bullosa syndrome

Takuji Masunaga, Hironori Niizeki, Fumiyo Yasuda, Kenji Yoshida, Masayuki Amagai, Akira Ishiko

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is a rare subgroup of epidermolysis bullosa, which is inherited disorder characterized by skin fragile. PA-JEB is caused by mutation of ITGB4 or ITGA6, which encodes integrin β4 or α6, respectively. Objective: To clarify the molecular basis of PA-JEB and to expand the mutational database, we carried out the mutational analysis of a 29-year-old Japanese PA-JEB patient. Methods: Standard methods were used to prepare, PCR-amplify, and sequence DNA or mRNA in peripheral blood or skin samples, respectively. Results: Sequence analysis revealed two novel mutations in ITGB4, c.264+2TtoA and c.1762-25TtoA. The paternal c.264+2TtoA resided within a splice site consensus region and generated two splice variants resulting in a premature termination codon (PTC). The maternal c.1762-25TtoA was a unique mutation because of its location, 25. bp away from the splice site, and resided in branch-point consensus sequence. This c.1762-25TtoA substitution resulted in generation of two abnormal transcripts each with a PTC. Genotype-phenotype correlation in this case was also unique because the proband showed a non-lethal phenotype regardless of both mutations resulted in only abnormal transcripts with a PTC. Conclusion: The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB.

Original languageEnglish
Pages (from-to)61-66
Number of pages6
JournalJournal of Dermatological Science
Volume78
Issue number1
DOIs
Publication statusPublished - 2015 Apr 1

Fingerprint

Junctional Epidermolysis Bullosa
Integrins
Skin
Substitution reactions
Nucleotides
Genes
Nonsense Codon
DNA sequences
Mutation
Genetic Association Studies
Blood
Messenger RNA
Databases
Epidermolysis Bullosa
Consensus Sequence
Rare Diseases
Sequence Analysis
Mothers
Pyloric Atresia
Phenotype

Keywords

  • Blister
  • Branch-point mutation
  • Genodermatosis
  • RT-PCR
  • Splice site mutation

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Molecular Biology

Cite this

Splicing abnormality of integrin β4 gene (ITGB4) due to nucleotide substitutions far from splice site underlies pyloric atresia-junctional epidermolysis bullosa syndrome. / Masunaga, Takuji; Niizeki, Hironori; Yasuda, Fumiyo; Yoshida, Kenji; Amagai, Masayuki; Ishiko, Akira.

In: Journal of Dermatological Science, Vol. 78, No. 1, 01.04.2015, p. 61-66.

Research output: Contribution to journalArticle

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abstract = "Background: Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is a rare subgroup of epidermolysis bullosa, which is inherited disorder characterized by skin fragile. PA-JEB is caused by mutation of ITGB4 or ITGA6, which encodes integrin β4 or α6, respectively. Objective: To clarify the molecular basis of PA-JEB and to expand the mutational database, we carried out the mutational analysis of a 29-year-old Japanese PA-JEB patient. Methods: Standard methods were used to prepare, PCR-amplify, and sequence DNA or mRNA in peripheral blood or skin samples, respectively. Results: Sequence analysis revealed two novel mutations in ITGB4, c.264+2TtoA and c.1762-25TtoA. The paternal c.264+2TtoA resided within a splice site consensus region and generated two splice variants resulting in a premature termination codon (PTC). The maternal c.1762-25TtoA was a unique mutation because of its location, 25. bp away from the splice site, and resided in branch-point consensus sequence. This c.1762-25TtoA substitution resulted in generation of two abnormal transcripts each with a PTC. Genotype-phenotype correlation in this case was also unique because the proband showed a non-lethal phenotype regardless of both mutations resulted in only abnormal transcripts with a PTC. Conclusion: The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB.",
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N2 - Background: Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is a rare subgroup of epidermolysis bullosa, which is inherited disorder characterized by skin fragile. PA-JEB is caused by mutation of ITGB4 or ITGA6, which encodes integrin β4 or α6, respectively. Objective: To clarify the molecular basis of PA-JEB and to expand the mutational database, we carried out the mutational analysis of a 29-year-old Japanese PA-JEB patient. Methods: Standard methods were used to prepare, PCR-amplify, and sequence DNA or mRNA in peripheral blood or skin samples, respectively. Results: Sequence analysis revealed two novel mutations in ITGB4, c.264+2TtoA and c.1762-25TtoA. The paternal c.264+2TtoA resided within a splice site consensus region and generated two splice variants resulting in a premature termination codon (PTC). The maternal c.1762-25TtoA was a unique mutation because of its location, 25. bp away from the splice site, and resided in branch-point consensus sequence. This c.1762-25TtoA substitution resulted in generation of two abnormal transcripts each with a PTC. Genotype-phenotype correlation in this case was also unique because the proband showed a non-lethal phenotype regardless of both mutations resulted in only abnormal transcripts with a PTC. Conclusion: The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB.

AB - Background: Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is a rare subgroup of epidermolysis bullosa, which is inherited disorder characterized by skin fragile. PA-JEB is caused by mutation of ITGB4 or ITGA6, which encodes integrin β4 or α6, respectively. Objective: To clarify the molecular basis of PA-JEB and to expand the mutational database, we carried out the mutational analysis of a 29-year-old Japanese PA-JEB patient. Methods: Standard methods were used to prepare, PCR-amplify, and sequence DNA or mRNA in peripheral blood or skin samples, respectively. Results: Sequence analysis revealed two novel mutations in ITGB4, c.264+2TtoA and c.1762-25TtoA. The paternal c.264+2TtoA resided within a splice site consensus region and generated two splice variants resulting in a premature termination codon (PTC). The maternal c.1762-25TtoA was a unique mutation because of its location, 25. bp away from the splice site, and resided in branch-point consensus sequence. This c.1762-25TtoA substitution resulted in generation of two abnormal transcripts each with a PTC. Genotype-phenotype correlation in this case was also unique because the proband showed a non-lethal phenotype regardless of both mutations resulted in only abnormal transcripts with a PTC. Conclusion: The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB.

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