Transcriptional regulatory defects in the first intron of Bruton's tyrosine kinase.
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.
Shin
Dong-Min
DM
Department of Microbiology, College of Medicine, Chungnam National University, Daejon, Korea.
Jo
Eun-Kyeong
EK
Kanegane
Hirokazu
H
Futatani
Takeshi
T
Zhao
Meina
M
Song
Chang-Hwa
CH
Yamagishi
Atsushi
A
Miyawaki
Toshio
T
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000201:enzymology / Q000235:genetics*; D001402:B-Lymphocytes / Q000201:enzymology; D041321:Chromosomes, Human, X; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics*; D014158:Transcription, Genetic
D005819:Genetic Markers; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human