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Characterization of Bruton's Tyrosine Kinase Genetic Mutations in One Korean X-linked Agammaglobulinemia Family

Journal of the Korean Pediatric Society 2002;45(2):183-191.
Published online February 15, 2002.
Characterization of Bruton's Tyrosine Kinase Genetic Mutations in One Korean X-linked Agammaglobulinemia Family
Eun-Kyeong Jo1, Chang-Hwa Song1, Jeong-Kyu Park1, Young-Jong Baek2, Hye-Young Rhu2, Jae-Ho Lee2, Tai-Ju Hwang3, Hoon Kook3
1Department of Microbiology, College of Medicine, Chungnam National University, Taejon, Korea
2Department of Pediatrics, College of Medicine, Chungnam National University, Taejon, Korea
3Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea
반성 열성 범저감마글로불린혈증 1가계 3환자의 Bruton's Tyrosine Kinase 유전자 변이 및 임상 양상
조은경1, 송창화1, 박정규1, 백영종2, 유혜영2, 이재호2, 황태주3, 국훈3
1충남대학교 의과대학 미생물학교실
2충남대학교 의과대학 소아과학교실
3전남대학교 의과대학 소아과학교실
Hoon Kook, Email: hoonkook@chonnam.ac.kr
: X-linked agammaglobulinemia(XLA) is an immunodeficiency caused by abnormalities in Bruton's tyrosine kinase(Btk), and is characterized by a deficiency of peripheral blood B cells. We studied the cytoplasmic expression of Btk protein and analyzed the Btk gene in peripheral blood mononuclear cells from two siblings and one cousin with XLA, as well as additional family members.
: Btk protein expression was analyzed by flow cytometry. Isolation of the coding sequence of the Btk gene was performed by amplification using the reverse transcription-polymerase chain reaction(RT-PCR) technique. Sequence alterations were screened by the single-stranded conformation polymorphism(SSCP) method and characterized by standard sequencing protocols.
: Cytoplasmic expression of Btk protein in monocytes was not detected in three patients with XLA. In addition, Btk protein analysis clearly showed cellular mosaicism in monocytes from four obligate carriers, findings further supported by SSCP. A single base pair mutation(T to C) in Btk-exon three, which encodes the PH domain, was identified in four XLA patients. A diagnostic sequencing analysis was established to detect heterozygotic pattern in 4 carrier females. Furthermore, we found significant clinical heterogeneity in individuals with the same gene mutation.
: The implicating genetic alteration provided valuable clues to the pathogenesis of XLA in Korea and the flow cytometric analysis was suggested as a useful tool for rapid detection of XLA patients and carriers. The present study has identified a genetic mutation in the Btk coding region and demonstrated heterogeneity in clinical manifestations among patients with the same mutation. A flow cytometric analysis was found to be informative in establishing a deficiency of Btk protein in both patients and carriers and is recommended as a frontline procedure in the molecular diagnosis and work-up of XLA.
Key Words: Bruton's tyrosine kinase, X-linked agammaglobulinemia, Direct sequencing, Flow cytometry, Carrier detection

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