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Transcriptional regulatory defects in the first intron of Bruton’s tyrosine kinase
Author(s) -
Shin DongMin,
Jo EunKyeong,
Kanegane Hirokazu,
Futatani Takeshi,
Zhao Meina,
Song ChangHwa,
Yamagishi Atsushi,
Miyawaki Toshio
Publication year - 2008
Publication title -
pediatrics international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.49
H-Index - 63
eISSN - 1442-200X
pISSN - 1328-8067
DOI - 10.1111/j.1442-200x.2008.02739.x
Subject(s) - bruton's tyrosine kinase , intron , gene , mutation , x linked agammaglobulinemia , mutant , microbiology and biotechnology , genetics , tyrosine kinase , reporter gene , hypogammaglobulinemia , biology , medicine , gene expression , antibody , signal transduction
Background: X‐linked agammaglobulinemia (XLA), characterized by the early onset of recurrent bacterial infections, profound hypogammaglobulinemia, and a markedly diminished number of peripheral B lymphocytes, is caused by mutations in the Bruton’s tyrosine kinase ( BTK ) gene. The >600 unique mutations identified to date include single base pair substitutions, small insertions or deletions, and gross deletions. A few cases, however, have been found to have no mutations in the coding region even with reduced BTK mRNA or protein expression. Mutations in intron 1 positions +5 (G→A) and +6 (T→G) of the BTK gene have been identified, and these changes were associated with reduced transcriptional activity. Methods: In the present study a novel mutation in intron 1 position +5 (G→T) was identified in a Japanese patient with XLA. The reporter constructs containing these mutations were made, and the reporter activities were measured using a luciferase assay. Results: All the mutant constructs were demonstrated to have reduced transcriptional activity. Conclusions: Positions +5 and +6 in intron 1 of the BTK gene are critical for transcriptional activity, and defects in these regions cause XLA.