Clinical and genetic profiles of patients with X-linked agammaglobulinemia from southeast Turkey: Novel mutations in BTK gene
Main Article Content
Keywords
Bruton tyrosine kinase, Genotype-phenotype correlation, X-linked agammaglobulinemia
Abstract
Background: X-linked agammaglobulinemia (XLA) is characterized by absent or severely reduced B cells, low or undetectable immunoglobulin levels, and clinically by extracellular bacterial infections which mainly compromise the respiratory tract. We aimed to analyze the clinical, immunological and genetic characteristics of 22 male children with XLA.
Methods: Twenty-two children with XLA from 12 unrelated families were enrolled in this study. Clinical and demographic features of patients, serum immunoglobulin levels, percentage of B cells and BTK gene mutations were reviewed retrospectively.
Results: We identified 12 different mutations in 22 patients from 12 unrelated families. The most frequent type of mutation was premature stop codon (33.3%). Ten mutations had been reported previously including three missense mutations (c.1774T>C, c.1684C>T, c.83G>T), three premature stop codons (c.1558C>T, c.1573C>T, c.753G>A), two splice-site (c.683-1G>A, c.1567- 12 1567-9delTTTG) and two small nucleotide deletions (c.902-904 delAAG, c.179 181delAGA). Two novel mutations of the BTK gene were also presented and included one splice-site mutation (c.391+1G>C) and one premature stop codon mutation (c.1243 1243delG). Six out of 12 mutations of the BTK gene were located in the SH1 domain, two in the PH domain, two in the SH3 domain and two in the SH2 domain. Three patients had a history of severe infection before diagnosis. We did not identify any correlation between severity of clinical symptoms and the genotype.
Conclusions: Our results show that mutations in southeast Turkey could be different from those in the rest of the world and molecular genetic tests are an important tool for early confirmed diagnosis of XLA.
References
2. Suri D, Rawat A, Singh S. X-linked agammaglobulinemia. Indian J Pediatr. 2016;83:331-7.
3. Aadam Z, Kechout N, Barakat A, Chan KW, Ben-Ali M, BenMustapha I, et al. X-linked agammagobulinemia in a large series of North African patients: frequency clinical features and novel BTK mutations. J Clin Immunol. 2016;36:187-94.
4. Degand N, Dautremer J, Pilmis B, Ferroni A, Lanternier F, Bruneau J, et al. Helicobacter bilis-associated suppurative cholangitis in a patient with X-linked agammaglobulinemia. J Clin Immunol. 2017;37:727-31.
5. Chen XF, Wang WF, Zhang YD, Zhao W, Wu J, Chen TX. Clinical characteristics and genetic profiles of 174 patients with X-linked agammaglobulinemia. Medicine. 2016;95:e4544.
6. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinemia is a member of the src family of protein-tyrosine kinases. J Nature. 1993;361:226-33.
7. Sideras P, Smith CIE. Molecular and cellular aspects of X-linked agammaglobulinemia. J Adv Immunol. 1995;59:135-223.
8. Hagemann TL, Chen Y, Rosen FS, et al. Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia. J Hum Mol Genet. 1994;3: 1743-9.
9. Rohrer J, Parolini O, Belmont JW, et al. The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia. J Immunogenet. 1994;40:319-24.
10. Broides A, Wenjian Y, Conley ME. Genotype/phenotype correlations in X-linked agammaglobulinemia. Clin Immunol. 2006;118:195-200.
11. Bykowsky MJ, Haire RN, Ohta Y, Tang H, Sung SS, Veksler ES, et al. Discordant phenotype in siblings with X-linked agammaglobulinemia. Am J Hum Genet. 1996;58:477-83.
12. Conley ME, Parolini O, Rohrer J, Campana D. X-linked agammaglobulinemia: new approaches to old questions based on the identification of the defective gene. Immunol Rev. 1994;138:5-21.
13. Kitanaka A, Mano H, Conley ME, Campana D. Expression and activation of the nonreceptor tyrosine kinase Tec in human B cells. Blood. 1998;91:940-8.
14. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93: 190-7.
15. García-García E, Staines-Boone AT, Vargas-Hernández A, González-Serrano ME, Carrillo-Tapia E, Mogica-Martínez D, et al. Clinical and mutational features of X-linked agammaglobulinemia in Mexico. Clin Immunol. 2016;165:38-44.
16. 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. Int Arch Allergy Immunol. 2006;141: 408-14.
17. Conley ME, Broides A, Hernandez-Trujillo V, Howard V, Kanegane H, Miyawaki T, Shurtleff SA. Genetic analysis of patients with defects in early B-cell development. Immunol Rev. 2005;203:216-34.
18. Wang Y, Kanegane H, Sanal O, Ersoy F, Tezcan I, Futatani T, et al. Bruton tyrosine kinase gene mutations in Turkish patients with presumed X-linked agammaglobulinemia. Hum Mutat. 2001;18:356-60.
19. Lopez-Herrera G, Berron-Ruiz L, Mogica-Martinez D, EspinosaRosales F, Santos-Argumedo L. Characterization of Bruton’s tyrosine kinase mutations in Mexican patients with X-linked agammaglobulinemia. Mol Immunol. 2008;45:1094-8.
20. Zhang ZY, Zhao XD, Jiang LP, Liu EM, Wang M, Yu J, et al. Clinical characteristics and molecular analysis of 21 Chinese children with congenital agammaglobulinemia. Scand J Immunol. 2010;72:454-9.
21. Wang Y, Kanegane H, Wang X, Han X, Zhang Q, Zhao S, et al. Mutation of the BTK gene and clinical feature of X-linked agammaglobulinemia in mainland China. J Clin Immunol. 2009;29:352-6.
22. Trakultivakorn M, Ochs HD. X-linked agammaglobulinemia in northern Thailand. Asian Pac J Allergy Immunol. 2006;24:57-63.
23. Noh LM, Ismail Z, Zainudin BM, Low SM, Azizi BH, Noah RM, Nasaruddin BA. Clinical patterns of X-linked agammaglobulinemia in Malaysian children. Acta Paediatr Jpn. 1995 Jun;37:331-5.
24. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, Ochs HD, Bonilla FA, Paris K, et al. Autoimmunity and inflammation in X linked agammaglobulinemia. J Clin Immunol. 2014;34:627-32.
25. 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. Clin Immunol. 2002;104:221-30.
26. Honda F, Kano H, Kanegane H, Nonoyama S, Kim ES, Lee SK, et al. The kinase Btk negatively regulates the production of reactive oxygen species and stimulation-induced apoptosis in human neutrophils. Nat Immunol. 2012;13:369-78.
27. Chun JK, Lee TJ, Song JW, Linton JA, Kim DS. Analysis of clinical presentations of Bruton disease: a review of 20 years of accumulated data from pediatric patients at Severance Hospital. Yonsei Med J. 2008;49:28-36.
28. Pamuk ON, Pamuk GE, Turgut B, C¸akır N. Scleroderma in a patient with X-linked agammaglobulinemia. Scand J Rheumatol. 2004;33:59-60.
29. Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, Ochs HD, Bonilla FA, et al. Autoimmunity and inflammation in X-linked agammaglobulinemia. J Clin Immunol. 2014;34: 627-32.
30. Careta MF, Romiti R. Localized scleroderma: clinical spectrum and therapeutic update. An Bras Dermatol. 2015;90:62-73.
31. Aksu G, Genel F, Koturo˘glu G, Kurugöl Z, Kütükc¸üler N. Serum immunoglobulin (IgG, IgM, IgA) and IgG subclass concentrations in healthy children: a study using nephelometric technique. Turk J Pediatr. 2006;48:19-24.
32. Esenboga S, C¸agdas D, Ozgur TT, Gur C¸etinkaya P, Turkdemir LM, Sanal O, et al. Clinical and genetic features of the patients with X-linked agammaglobulinemia from Turkey: single-center experience. Scand J Immunol. 2018;9, http://dx.doi.org/10.1111/sji.12647.
33. Kobayashi S, Iwata T, Saito M, Iwasaki R, Matsumoto H, Naritaka S, et al. Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan. Hum Genet. 1996;97:424-30.
34. López-Granados E, Pérez de Diego R, Ferreira Cerdán A, Fontán Casariego G, García Rodríguez MC. A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia. J Allergy Clin Immunol. 2005;116:690-7.
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.