Differential Expression and Phosphorylation of BTK Protein Domain in X-linked Agammaglobulinemia
-
Mahsa Sohani
,
Samaneh Delavari
,
Amir Hassan Zarnani
,
Leila Parvaneh
,
Shima Rasouli
,
Sepideh Shahkarami
,
Sepideh Babaie
,
Fatemeh Kiaee
Abstract
Background/objectives: X-linked (Bruton’s) agammaglobulinemia (XLA) is a rare congenital disorder with defects in early B cell development caused by mutations in the gene encoding BTK (Bruton tyrosine kinase). The aim of this study was to investigate the expression and phosphorylation of BTK protein domain in these patients.
Methods: A total of 19 patients with mutations in BTK gene were analyzed for the expression and phosphorylation of BTK protein through immunoblotting. The correlations between BTK expression and the results of immunoblotting as well as clinical and immunologic phenotypes were evaluated.
Results: Six patients showed normal expression of protein and phosphorylation of BTK and two patients had normal phosphorylation while no expression was observed. There was a significant difference between the groups of patients with normal expression of protein and those without it (p=0.01).
Conclusion: Since we identified 6 patients with normal expression and phosphorylation of BTK, and two patients with normal phosphorylation but no expression, thus more studies should be done in order to explore other aspects of the disease. Although there was not any significant correlation between the severity of clinical manifestations and BTK expression, further investigations are necessary to determine the compensatory mechanisms in XLA patients.
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6. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Clinical,immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clinical immunology. 2002 Sep;104(3):221-30. PubMed PMID: 12217331.
7. Pac M, Bernatowska EA, Kierkus J, Ryzko JP, Cielecka-Kuszyk J, Jackowska T, et al. Gastrointestinal disorders next to respiratory infections as leading symptoms of X-linked agammaglobulinemia in children - 34-year experience of a single center. Archives of medical science : AMS. 2017 Mar 1;13(2):412-7. PubMed PMID: 28261296. Pubmed Central PMCID: PMC5332446. Epub 2017/03/07. eng.
8. Gaspar HB, Lester T, Levinsky RJ, Kinnon C. Bruton's tyrosine kinase expression and activity in X-linked agammaglobulinaemia (XLA): the use of protein analysis as a diagnostic indicator of XLA. Clinical and experimental immunology. 1998 Feb;111(2):334-8. PubMed PMID: 9486400. Pubmed Central PMCID: 1904924.
9. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunological reviews. 2009 Mar;228(1):58-73. PubMed PMID: 19290921.
10. Aghamohammadi A, Fiorini M, Moin M, Parvaneh N, Teimourian S, Yeganeh M, et al. Clinical, immunological and molecular characteristics of 37 Iranian patients with X-linked agammaglobulinemia. International archives of allergy and immunology. 2006;141(4):408-14. PubMed PMID: 16943681.
11. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in Xlinked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226-33. PubMed PMID: 8380905. Epub 1993/01/21. eng.
12. Ohta Y, Haire RN, Litman RT, Fu SM, Nelson RP, Kratz J, et al. Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. Proceedings of the National Academy of Sciences of the United States of America. 1994 Sep 13;91(19):9062-6. PubMed PMID: 8090769. Pubmed Central PMCID: PMC44747. Epub 1994/09/13. eng.
13. Sediva A, Smith CI, Asplund AC, Hadac J, Janda A, Zeman J, et al. Contiguous Xchromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. Journal of clinical immunology. 2007 Nov;27(6):640-6. PubMed PMID: 17851739.
14. Abolhassani H, Vitali M, Lougaris V, Giliani S, Parvaneh N, Parvaneh L, et al. Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects. Expert review of clinical immunology. 2016;12(4):479-86. PubMed PMID: 26910880. Epub 2016/02/26. eng.
15. Lopez-Granados E, Perez de Diego R, Ferreira Cerdan A, Fontan Casariego G, Garcia Rodriguez MC. A genotype-phenotype correlation study in a group of 54 patients with X-linkedagammaglobulinemia. The Journal of allergy and clinical immunology. 2005 Sep;116(3):690-7. PubMed PMID: 16159644.
16. Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. The Journal of biological chemistry. 2003 Jul 11;278(28):26258- 64. PubMed PMID: 12724322.
17. Broides A, Yang W, Conley ME. Genotype/phenotype correlations in X-linked agammaglobulinemia. Clinical immunology. 2006 Feb-Mar;118(2-3):195-200. PubMed PMID: 16297664.
18. Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, et al. Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood. 1996 Jul 15;88(2):561-73. PubMed PMID: 8695804.
19. Takashima T, Okamura M, Yeh TW, Okano T, Yamashita M, Tanaka K, et al. Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases. Journal of clinical immunology. 2017 Jun 08. PubMed PMID: 28597144.
20. Dsouza A, Scofield RH. Protein Stains to Detect Antigen on Membranes. Methods in molecular biology. 2015;1314:33-40. PubMed PMID: 26139252.
21. Grimbacher B, Party ERW. The European Society for Immunodeficiencies (ESID) registry 2014. Clinical and experimental immunology. 2014 Dec;178 Suppl 1:18-20. PubMed PMID: 25546747. Pubmed Central PMCID: 4285476.
22. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan 29;72(2):279-90. PubMed PMID: 8425221. Epub 1993/01/29. eng.
23. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clinical reviews in allergy & immunology. 2000 Oct;19(2):183-204. PubMed PMID: 11107501.
24. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, et al. Genetic analysis of patients with defects in early B-cell development. Immunological reviews. 2005 Feb;203:216-34. PubMed PMID: 15661032.
25. Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G. NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proceedings of the National Academy of Sciences of the United States of America. 1999 Aug 03;96(16):9136-41. PubMed PMID: 10430908. Pubmed Central PMCID: 17745.
26. Bendall HH, Sikes ML, Ballard DW, Oltz EM. An intact NF-kappa B signaling pathway is required for maintenance of mature B cell subsets. Molecular immunology. 1999 Feb;36(3):187-95. PubMed PMID: 10403484.27. Grumont RJ, Rourke IJ, O'Reilly LA, Strasser A, Miyake K, Sha W, et al. B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. The Journal of experimental medicine. 1998 Mar 02;187(5):663-74. PubMed PMID: 9480976. Pubmed Central PMCID: 2212175.
28. Kontgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlinton D, et al. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin2 expression. Genes & development. 1995 Aug 15;9(16):1965-77. PubMed PMID: 7649478.
29. Kanegane H, Futatani T, Wang Y, Nomura K, Shinozaki K, Matsukura H, et al. Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. The Journal of allergy and clinical immunology. 2001 Dec;108(6):1012-20. PubMed PMID: 11742281.
30. Kawakami Y, Miura T, Bissonnette R, Hata D, Khan WN, Kitamura T, et al. Bruton's tyrosine kinase regulates apoptosis and JNK/SAPK kinase activity. Proceedings of the National Academy of Sciences of the United States of America. 1997 Apr 15;94(8):3938-42. PubMed PMID: 9108083. Pubmed Central PMCID: 20546.
31. Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Backesjo CM, et al. Mutation screening of the BTK gene in 56 families with Xlinked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998 Feb;101(2):276-84. PubMed PMID: 9445504.
32. Wood PM, Mayne A, Joyce H, Smith CI, Granoff DM, Kumararatne DS. A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency. The Journal of pediatrics. 2001 Jul;139(1):148-51. PubMed PMID: 11445810. Epub 2001/07/11. eng.
33. Noordzij JG, de Bruin-Versteeg S, ComansBitter WM, Hartwig NG, Hendriks RW, de Groot R, et al. Composition of precursor B-cell compartment in bone marrow from patients with X-linked agammaglobulinemia compared with healthy children. Pediatric research. 2002 Feb;51(2):159-68. PubMed PMID: 11809909. Epub 2002/01/26. eng.
34. Cooke A. Infection and autoimmunity. Blood cells, molecules & diseases. 2009 MarApr;42(2):105-7. PubMed PMID: 19027331. Epub 2008/11/26. eng.
35. Blackmore S, Hernandez J, Juda M, Ryder E, Freund GG, Johnson RW, et al. Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America. 2017 Jul 25;114(30):E6107-E16. PubMed PMID: 28696309. Pubmed Central PMCID: PMC5544260. Epub 2017/07/12. eng.
36. Crompot E, Van Damme M, Duvillier H, Pieters K, Vermeesch M, Perez-Morga D, et al. Avoiding false positive antigen detection by flowcytometry on blood cell derived microparticles: the importance of an appropriate negative control. PloS one. 2015;10(5):e0127209. PubMed PMID: 25978814. Pubmed Central PMCID: 4433223.
37. Lopez -Herrera G, Berron -Ruiz L, Mogica - Martinez D, Espinosa -Rosales F, Santos - Argumedo L. Characterization of Bruton's tyrosine kinase mutations in Mexican patients with X -linked agammaglobulinemia. Molecular immunology. 2008 Feb;45(4):1094 -8. PubMed PMID: 17765309.
38. Tani SM, Wang Y, Kanegane H, Futatani T, Pinto J, Vilela MM, et al. Identification of mutations of Bruton's tyrosine kinase gene (BTK) in Brazilian patients with X -linked agammaglobulinemia. Human mutation. 2002 Sep;20(3):235 -6. PubMed PMID: 12204007.
2. Joshi AY, Iyer VN, Hagan JB, St Sauver JL, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clinic proceedings. 2009;84(1):16-22. PubMed PMID: 19121249. Pubmed Central PMCID: 2630110.
3. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. Journal of clinical immunology. 2007 Sep;27(5):497-502. PubMed PMID: 17577648.
4. Vihinen M, Brandau O, Branden LJ, Kwan SP, Lappalainen I, Lester T, et al. BTKbase, mutation database for X-linked agammaglobulinemia (XLA). Nucleic acids research. 1998 Jan 01;26(1):242-7. PubMed PMID: 9399844. Pubmed Central PMCID: 147244.
5. Graziani S, Di Matteo G, Benini L, Di Cesare S, Chiriaco M, Chini L, et al. Identification of a Btk mutation in a dysgammaglobulinemic patient with reduced B cells: XLA diagnosis or not? Clinical immunology. 2008 Sep;128(3):322-8. PubMed PMID: 18708023.
6. Plebani A, Soresina A, Rondelli R, Amato GM, Azzari C, Cardinale F, et al. Clinical,immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study. Clinical immunology. 2002 Sep;104(3):221-30. PubMed PMID: 12217331.
7. Pac M, Bernatowska EA, Kierkus J, Ryzko JP, Cielecka-Kuszyk J, Jackowska T, et al. Gastrointestinal disorders next to respiratory infections as leading symptoms of X-linked agammaglobulinemia in children - 34-year experience of a single center. Archives of medical science : AMS. 2017 Mar 1;13(2):412-7. PubMed PMID: 28261296. Pubmed Central PMCID: PMC5332446. Epub 2017/03/07. eng.
8. Gaspar HB, Lester T, Levinsky RJ, Kinnon C. Bruton's tyrosine kinase expression and activity in X-linked agammaglobulinaemia (XLA): the use of protein analysis as a diagnostic indicator of XLA. Clinical and experimental immunology. 1998 Feb;111(2):334-8. PubMed PMID: 9486400. Pubmed Central PMCID: 1904924.
9. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunological reviews. 2009 Mar;228(1):58-73. PubMed PMID: 19290921.
10. Aghamohammadi A, Fiorini M, Moin M, Parvaneh N, Teimourian S, Yeganeh M, et al. Clinical, immunological and molecular characteristics of 37 Iranian patients with X-linked agammaglobulinemia. International archives of allergy and immunology. 2006;141(4):408-14. PubMed PMID: 16943681.
11. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in Xlinked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226-33. PubMed PMID: 8380905. Epub 1993/01/21. eng.
12. Ohta Y, Haire RN, Litman RT, Fu SM, Nelson RP, Kratz J, et al. Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia. Proceedings of the National Academy of Sciences of the United States of America. 1994 Sep 13;91(19):9062-6. PubMed PMID: 8090769. Pubmed Central PMCID: PMC44747. Epub 1994/09/13. eng.
13. Sediva A, Smith CI, Asplund AC, Hadac J, Janda A, Zeman J, et al. Contiguous Xchromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes. Journal of clinical immunology. 2007 Nov;27(6):640-6. PubMed PMID: 17851739.
14. Abolhassani H, Vitali M, Lougaris V, Giliani S, Parvaneh N, Parvaneh L, et al. Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects. Expert review of clinical immunology. 2016;12(4):479-86. PubMed PMID: 26910880. Epub 2016/02/26. eng.
15. Lopez-Granados E, Perez de Diego R, Ferreira Cerdan A, Fontan Casariego G, Garcia Rodriguez MC. A genotype-phenotype correlation study in a group of 54 patients with X-linkedagammaglobulinemia. The Journal of allergy and clinical immunology. 2005 Sep;116(3):690-7. PubMed PMID: 16159644.
16. Jefferies CA, Doyle S, Brunner C, Dunne A, Brint E, Wietek C, et al. Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. The Journal of biological chemistry. 2003 Jul 11;278(28):26258- 64. PubMed PMID: 12724322.
17. Broides A, Yang W, Conley ME. Genotype/phenotype correlations in X-linked agammaglobulinemia. Clinical immunology. 2006 Feb-Mar;118(2-3):195-200. PubMed PMID: 16297664.
18. Hashimoto S, Tsukada S, Matsushita M, Miyawaki T, Niida Y, Yachie A, et al. Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan. Blood. 1996 Jul 15;88(2):561-73. PubMed PMID: 8695804.
19. Takashima T, Okamura M, Yeh TW, Okano T, Yamashita M, Tanaka K, et al. Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases. Journal of clinical immunology. 2017 Jun 08. PubMed PMID: 28597144.
20. Dsouza A, Scofield RH. Protein Stains to Detect Antigen on Membranes. Methods in molecular biology. 2015;1314:33-40. PubMed PMID: 26139252.
21. Grimbacher B, Party ERW. The European Society for Immunodeficiencies (ESID) registry 2014. Clinical and experimental immunology. 2014 Dec;178 Suppl 1:18-20. PubMed PMID: 25546747. Pubmed Central PMCID: 4285476.
22. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan 29;72(2):279-90. PubMed PMID: 8425221. Epub 1993/01/29. eng.
23. Conley ME, Rohrer J, Minegishi Y. X-linked agammaglobulinemia. Clinical reviews in allergy & immunology. 2000 Oct;19(2):183-204. PubMed PMID: 11107501.
24. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, et al. Genetic analysis of patients with defects in early B-cell development. Immunological reviews. 2005 Feb;203:216-34. PubMed PMID: 15661032.
25. Lee HH, Dadgostar H, Cheng Q, Shu J, Cheng G. NF-kappaB-mediated up-regulation of Bcl-x and Bfl-1/A1 is required for CD40 survival signaling in B lymphocytes. Proceedings of the National Academy of Sciences of the United States of America. 1999 Aug 03;96(16):9136-41. PubMed PMID: 10430908. Pubmed Central PMCID: 17745.
26. Bendall HH, Sikes ML, Ballard DW, Oltz EM. An intact NF-kappa B signaling pathway is required for maintenance of mature B cell subsets. Molecular immunology. 1999 Feb;36(3):187-95. PubMed PMID: 10403484.27. Grumont RJ, Rourke IJ, O'Reilly LA, Strasser A, Miyake K, Sha W, et al. B lymphocytes differentially use the Rel and nuclear factor kappaB1 (NF-kappaB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. The Journal of experimental medicine. 1998 Mar 02;187(5):663-74. PubMed PMID: 9480976. Pubmed Central PMCID: 2212175.
28. Kontgen F, Grumont RJ, Strasser A, Metcalf D, Li R, Tarlinton D, et al. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin2 expression. Genes & development. 1995 Aug 15;9(16):1965-77. PubMed PMID: 7649478.
29. Kanegane H, Futatani T, Wang Y, Nomura K, Shinozaki K, Matsukura H, et al. Clinical and mutational characteristics of X-linked agammaglobulinemia and its carrier identified by flow cytometric assessment combined with genetic analysis. The Journal of allergy and clinical immunology. 2001 Dec;108(6):1012-20. PubMed PMID: 11742281.
30. Kawakami Y, Miura T, Bissonnette R, Hata D, Khan WN, Kitamura T, et al. Bruton's tyrosine kinase regulates apoptosis and JNK/SAPK kinase activity. Proceedings of the National Academy of Sciences of the United States of America. 1997 Apr 15;94(8):3938-42. PubMed PMID: 9108083. Pubmed Central PMCID: 20546.
31. Holinski-Feder E, Weiss M, Brandau O, Jedele KB, Nore B, Backesjo CM, et al. Mutation screening of the BTK gene in 56 families with Xlinked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course. Pediatrics. 1998 Feb;101(2):276-84. PubMed PMID: 9445504.
32. Wood PM, Mayne A, Joyce H, Smith CI, Granoff DM, Kumararatne DS. A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency. The Journal of pediatrics. 2001 Jul;139(1):148-51. PubMed PMID: 11445810. Epub 2001/07/11. eng.
33. Noordzij JG, de Bruin-Versteeg S, ComansBitter WM, Hartwig NG, Hendriks RW, de Groot R, et al. Composition of precursor B-cell compartment in bone marrow from patients with X-linked agammaglobulinemia compared with healthy children. Pediatric research. 2002 Feb;51(2):159-68. PubMed PMID: 11809909. Epub 2002/01/26. eng.
34. Cooke A. Infection and autoimmunity. Blood cells, molecules & diseases. 2009 MarApr;42(2):105-7. PubMed PMID: 19027331. Epub 2008/11/26. eng.
35. Blackmore S, Hernandez J, Juda M, Ryder E, Freund GG, Johnson RW, et al. Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis. Proceedings of the National Academy of Sciences of the United States of America. 2017 Jul 25;114(30):E6107-E16. PubMed PMID: 28696309. Pubmed Central PMCID: PMC5544260. Epub 2017/07/12. eng.
36. Crompot E, Van Damme M, Duvillier H, Pieters K, Vermeesch M, Perez-Morga D, et al. Avoiding false positive antigen detection by flowcytometry on blood cell derived microparticles: the importance of an appropriate negative control. PloS one. 2015;10(5):e0127209. PubMed PMID: 25978814. Pubmed Central PMCID: 4433223.
37. Lopez -Herrera G, Berron -Ruiz L, Mogica - Martinez D, Espinosa -Rosales F, Santos - Argumedo L. Characterization of Bruton's tyrosine kinase mutations in Mexican patients with X -linked agammaglobulinemia. Molecular immunology. 2008 Feb;45(4):1094 -8. PubMed PMID: 17765309.
38. Tani SM, Wang Y, Kanegane H, Futatani T, Pinto J, Vilela MM, et al. Identification of mutations of Bruton's tyrosine kinase gene (BTK) in Brazilian patients with X -linked agammaglobulinemia. Human mutation. 2002 Sep;20(3):235 -6. PubMed PMID: 12204007.
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| Issue | Vol 2, No 2 (2019) | |
| Section | Original Article | |
| DOI | https://doi.org/10.22034/igj.2019.189801.1013 | |
| Keywords | ||
| X-linked Agammaglobulinemia Bruton's tyrosine kinase protein expression and phosphorylation | ||
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How to Cite
1.
Sohani M, Delavari S, Zarnani AH, Parvaneh L, Rasouli S, Shahkarami S, Babaie S, Kiaee F. Differential Expression and Phosphorylation of BTK Protein Domain in X-linked Agammaglobulinemia. Immunol Genet J. 2019;2(2):58-71.
