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


CONCLUSIONS
The present case expands the mutational database and further elucidates the genotype-phenotype correlation for this rare disease, PA-JEB.
Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 162-8582, Japan; Research Laboratories, KOSÉ Corporation, 48-18, Sakae-cho, Kita-ku, Tokyo 114-0005, Japan. Electronic address: masunaga@z3.keio.jp.
Takuji
T
Masunaga
Department of Dermatology, National Center for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan.
Hironori
H
Niizeki
Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 162-8582, Japan.
Fumiyo
F
Yasuda
Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
Kenji
K
Yoshida
Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 162-8582, Japan.
Masayuki
M
Amagai
Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 162-8582, Japan; Department of Dermatology, School of Medicine, Faculty of Medicine, Toho University, 6-11-1, Omori-nishi, Ota-ku, Tokyo 143-8541, Japan.
Akira
A
Ishiko
D000328:Adult; D001706:Biopsy; D004252:DNA Mutational Analysis / Q000379:methods; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D039663:Integrin beta4 / Q000032:analysis / Q000235:genetics*; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D010641:Phenotype; D012326:RNA Splicing; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000737:chemistry / Q000648:ultrastructure
D005819:Genetic Markers; C059834:ITGB4 protein, human; D039663:Integrin beta4
Blister; Branch-point mutation; Genodermatosis; RT-PCR; Splice site mutation