Abstract
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent bacterial infections, hypogammaglobulinemia and low to normal numbers of circulating B cells. Mutations in the ICOS, TACI and CD19 genes have recently been identified in <10% of CVID patients. We, herein, describe two novel CD19 gene disruptions in an 8-year-old Japanese boy, who had been clinically diagnosed as having CVID at the age of 5 years. Flow-cytometric analysis demonstrated absence of CD19 and reduced CD21 expression on CD20-postive peripheral blood B cells. Mutation analysis of CD19 revealed a mutation in the splice acceptor site of intron 5 (IVS5-1G>T) of the maternal allele, resulting in skipping of exon 6, and a truncated protein product. The paternal allele was disrupted by a gross deletion encompassing at least the ATP2A1, CD19 and NFATC2IP genes. The patient had a small number of IgD− CD27+ memory B cells, in which somatic mutation were detected. His B cells showed substantial proliferation upon stimulation, but reduced IgG and IgA production in vitro. These findings extend the mutation spectrum of the CD19 deficiency to four, and confirm the homogeneity of the CD19 deficiency as a unique type of CVID.
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References
Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol 1999; 118 (Suppl 1): 1–28.
Hammarstrom L, Smith CIE . Genetic approach to common variable immunodeficiency and IgA deficiency. In: Ochs HD, Smith CIE, Puck JM (eds). Primary Immunodeficiency Diseases, 2nd edn. Oxford University Press: New York, USA, 2007, pp 313–325.
Kanegane H, Tsukada S, Iwata T, Futatani T, Nomura K, Yamamoto J et al. Detection of Bruton's tyrosine kinase mutations in hypogammaglobulinaemic males registered as common variable immunodeficiency (CVID) in the Japanese Immunodeficiency Registry. Clin Exp Immunol 2000; 120: 512–517.
Weston SA, Prasad ML, Mullighan CG, Chapel H, Benson EM . Assessment of male CVID patients for mutations in the Btk gene: how many have been misdiagnosed? Clin Exp Immunol 2001; 124: 465–469.
Aruffo A, Hollenbaugh D, Wu LH, Ochs HD . The molecular basis of X-linked agammaglobulinemia, hyper-IgM syndrome, and sever combined immunodeficiency in human. Curr Opin Hematol 1994; 1: 12–18.
Morra M, Silander O, Calpe S, Choi M, Oettgen H, Myers L et al. Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. Blood 2001; 98: 1321–1325.
Soresina A, Lougaris V, Giliani S, Cardinale F, Armenio L, Cattalini M et al. Mutations of the X-linked lymphoproliferative disease gene SH2D1A mimicking common variable immunodeficiency. Eur J Pediatr 2002; 161: 656–659.
Salzer U, Chapel HM, Webster ADB, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in human. Nat Genet 2005; 7: 820–828.
Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005; 37: 829–834.
Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003; 4: 261–268.
van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJM, van Tol MJD et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 2006; 354: 1901–1912.
Carter RH, Fearon DT . CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 1992; 256: 105–107.
van Noesel CJ, Lankester AC, van Lier RA . Dual antigen recognition by B cells. Immunol Today 1993; 14: 8–11.
Conley ME, Notarangelo LD, Etzioni A . Diagnostic criteria for primary immunodeficiencies. Clin Immunol 1999; 93: 190–197.
Agematsu K, Futatani T, Hokibara S, Kobayashi N, Takamoto M, Tsukada S et al. Absence of memory B cells in patients with common variable immunodeficiency. Clin Immunol 2002; 103: 34–42.
Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck G et al. Severe deficiency of switched memory B cells (CD27+ IgM− IgD−) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 2002; 99: 1544–1551.
Bradbury LE, Goldmacher VS, Tedder TF . The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13. J Immunol 1993; 151: 2915–2927.
Odermatt A, Taschner PE, Khanna VK, Busch HF, Karpati G, Jablexki CK et al. Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet 1996; 14: 191–194.
Rump JA, Thiel J, Nikolopoulos E, Aichem A, Illges H, Risch P et al. First case of human CD21 deficiency presenting with hypogammaglobulinemia but virtually normal specific antibody production upon vaccination. XIIth Meeting of the European Society for Immunodeficiencies. 2006; 4–7 October; Budapest (Abstract O25).
Agematsu K, Nagumo H, Shinozaki K, Hokibara S, Yasui K, Kawamura N et al. Absence of IgD− CD27+ memory B cell population in X-linked hyper-IgM syndrome. J Clin Invest 1998; 102: 853–860.
Czerkinsky CC, Nilsson LA, Nygren H, Ouchterlony O, Tarkowski A . A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Meth 1983; 65: 109–121.
Fayette J, Dubois B, Vandenabeele S, Bridon J-M, Vanbervliet B, Durand I et al. Human dendritic cells skew isotype switching of CD40-activated naïve B cells towards IgA1 and IgA2 . J Exp Med 1997; 185: 1909–1918.
Acknowledgements
We thank Ms Chikako Sakai, Ms Junko Michino, Mr Hitoshi Moriuchi and Dr Shunji Yamamori for their excellent technical assistance. This study was supported by a Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports and Technology, Japan, and grants from the Ministry of Health, Labour and Welfare, Japan. MCvZ was supported by Grant 349 from the foundation ‘Sophia Kinderziekenhuis Fonds’. The authors have no financial conflict of interest.
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Kanegane, H., Agematsu, K., Futatani, T. et al. Novel mutations in a Japanese patient with CD19 deficiency. Genes Immun 8, 663–670 (2007). https://doi.org/10.1038/sj.gene.6364431
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DOI: https://doi.org/10.1038/sj.gene.6364431
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