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Variable phenotypic expression of mutations in genes of the immune system
Rebecca H. Buckley
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
Address correspondence to: Rebecca Buckley, Box 2898, Duke University Medical Center, Durham, North Carolina 27710, USA. Phone: (919) 684-2922; Fax: (919) 681-7979; E-mail: buckL003@mc.duke.edu.
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Published November 1, 2005 - More info
J Clin Invest. 2005;115(11):2974–2976. https://doi.org/10.1172/JCI26956.
© 2005 The American Society for Clinical Investigation
Human primary immunodeficiency diseases have been recognized for only a little over a half century (1). The spectrum of such diseases has grown at an extremely rapid pace during the past 50 years, with currently more than 120 different syndromes having been described (2). For most of that period, the conditions were identified by their clinical and immunologic presentations. However, for the past 12 years, they have been defined extensively at a molecular level. Because making a firm diagnosis by clinical and immunologic criteria has always been problematic due to variability in presentation, it was thought that molecular testing would remove this ambiguity. The report by de Villartay et al. in this issue of the JCI clearly indicates that is not always the case (3). In the pre-molecular diagnostic period, there had been examples within sibships of clinical variability in expression of primary immunodeficiency. One of these was in a family reported by de Saint-Basile et al. (4) in which one sibling had Omenn syndrome and another had SCID. Subsequently, the explanation for this was found when mutations in recombination activating genes 1 and 2 (RAG1 and RAG2, respectively) were found to cause SCID (5), and later hypomorphic mutations in these genes were found to cause Omenn syndrome (6). It was then found that identical mutations in these genes could cause either syndrome (7). De Villartay and his colleagues (3) now show that another distinct clinical syndrome can be caused by hypomorphic mutations in RAG genes. In contrast to infants with SCID or Omenn syndrome due to RAG mutations, the infants in the current report had autoimmune cytopenias, B cells, normal Ig levels, clonal T cells with γδ TCRs, normal T cell proliferation, and only slightly elevated NK cell levels. Because all of the infants had disseminated CMV infections, the authors suggest that the expansion of Tiγδ T cells (where Ti represents the TCR expressing the γδ heterodimer) was due to stimulation by the CMV virus. As the authors point out, there is mounting evidence that T cells with γδ receptors have a role in host defense against several microbial pathogens, and they have been found to be increased in immunocompromised humans infected with CMV after transplantation. Thus, it is possible that environmental or other genetic factors modify the clinical manifestation of such mutations.
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Other genes with phenotypic variability
Other genes of the immune system in which mutations result in variable phenotypes include those that encode Bruton tyrosine kinase (BTK), Wiskott-Aldrich syndrome protein (WASP), signaling lymphocyte activation molecule–associated (SLAM-associated) protein (SAP), CD3 ε chain (CD3ε), common γ chain (γc), adenosine deaminase (ADA), and Jak3 (Table 1). These genes encode proteins essential for: (a) B cell development and function (BTK); (b) T cell development and signaling (CD3ε); (c) T cell function and survival (ADA); (d) cytokine receptor signaling (γc and Jak3); (e) regulation of cell signaling (SAP); and (f) intracellular signaling and actin polymerization (WASP). Usually, but not always, the phenotypic variability is due to the type and location of the mutation, with hypomorphic mutations causing a less complete immunodeficiency. In the CBA/N mouse, a mutation in the Btk gene results in polysaccharide antibody deficiency, whereas such mutations in humans usually cause agammaglobulinemia (8). However, there is a report of a human with only polysaccharide antibody deficiency who had a mutation in this gene (9). Mutations in the WASP gene result in Wiskott-Aldrich syndrome but also in X-linked thrombocytopenia (10). SH2D1A mutations have been shown to cause variously fatal infectious mononucleosis, common variable immunodeficiency (11), or hemophagocytic lymphohistiocytosis (12). Mutations in CD3ε were first reported to cause a relatively mild form of immunodeficiency (13), but more deleterious mutations were later found to cause SCID (14). Mutations in the genes encoding γc, ADA, and Jak3 usually result in SCID (15) but have also been shown to cause less severe forms of immunodeficiency (16–18).
Clinical ambiguity also arises from the fact that seemingly identical clinical syndromes can be caused by mutations in different immune system genes. For example, it was recently shown that Omenn syndrome can also be caused by mutations in the Artemis gene that encodes a DNA repair factor (19). Other conditions include the hyper-IgM syndrome that can be caused by mutations in at least 6 different genes (20) and SCID, known to be caused by mutations in at least 10 different genes (15, 21). The most striking example of this will likely be the syndrome of common variable immunodeficiency that promises to have many different molecular causes, including mutations in genes that encode SAP (11), inducible costimulator (ICOS) (22), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (23), and the CD40 ligand (20).
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