IngentaConnect Transcriptional regulatory defects in the first intron of Brutons...

Authors: Shin, Dong-Min; Jo, Eun-Kyeong; Kanegane, Hirokazu; Futatani, Takeshi¹; Zhao, Meina¹; Song, Chang-Hwa; Yamagishi, Atsushi²; Miyawaki, Toshio¹

Source: Pediatrics International, Volume 50, Number 6, December 2008 , pp. 801-805(5)

Publisher: Blackwell Publishing

Abstract:

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.

Keywords: Bruton's tyrosine kinase; intron 1; transcriptional regulatory elements; X-linked agammaglobulinemia

Document Type: Research article

DOI: 10.1111/j.1442-200X.2008.02739.x

Affiliations: 1: Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama 2: Department of Pediatrics, Takayama Red Cross Hospital, Takayama, Japan

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Transcriptional regulatory defects in the first intron of Bruton's tyrosine kinase