Abstract
Common variable immunodeficiency (CVID) is an antibody deficiency syndrome that often co-occurs in families with selective IgA deficiency (IgAD). Vořechovský et al. (Am J Hum Genet 64:1096–1109, 1999; J Immunol 164:4408–4416, 2000) ascertained and genotyped 101 multiplex IgAD families and used them to identify and fine map the IGAD1 locus on chromosome 6p. We analyzed the original genotype data in a subset of families with at least one case of CVID and present evidence of a CVID locus on chromosome 16q with autosomal dominant inheritance. The peak (model-based) LOD score for the best marker D16S518 is 2.83 at θ=0.07, and a 4-marker LOD score under heterogeneity peaks at 3.00 with α=0.68. The (model-free) NPL score using the same markers peaks at the same location with a value of 3.38 (P=0.0001).
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References
Braig DU, Schäffer AA, Glocker E, Salzer U, Warnatz K, Peter HH, Grimbacher B (2003) Linkage of autosomal dominant common variable immunodeficiency to chromosome 5p and evidence for locus heterogeneity. Hum Genet 112:369–378
Bruton OC (1952) Agammaglobulinemia. Pediatrics 9:722
Carvalho Neves Forte W, Ferreira De Carvalho Junior F, Damaceno N, Vidal Perez F, Gonzales Lopes C, Mastroti RA (2000) Evolution of IgA deficiency to IgG subclass deficiency and common variable immunodeficiency. Allergol Immunopathol 28:18–20
Castigli E, Wilson SA, Garibyan L, Raschid R, Bonilla F, Schneider L, Geha RS (2005) TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 37:829–834
Chang N-S, Pratt N, Heath J, Schultz L, Sleve D, Carey GB, Zevotek N (2001) Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity. J Biol Chem 276:3361–3370
Cottingham RW Jr, Idury RM, Schäffer AA (1993) Faster sequential genetic linkage computations. Am J Hum Genet 53:252–263
Cucca F, Zhu Z-B, Khanna A, Cossu F, Congia M, Badiali M, Lampis R, Frau F, De Virgiliis S, Cao A, Arnone M, Piras P, Campbell RD, Cooper MD, Volanakis JE, Powis SH (1998) Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region. Clin Exp Immunol 111:76–80
Davis S, Schroeder M, Goldin LR, Weeks DE (1996) Nonparametric simulation-based statistics for detecting linkage in general pedigrees. Am J Hum Genet 58:867–880
Español T, Catala M, Hernandez M, Caragol I, Bertran JM (1996) Development of a common variable immunodeficiency in IgA-deficient patients. Clin Immunol Immunopathol 80:333–335
Franco JL et al (2004) Common variable immunodeficiency (CVID) due to a homozygous mutation in the CD19 gene. The XIth Meeting of the European Society for Immunodeficiency, Versailles (Abstract #B71)
Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer AA, Mages HW, Kroczek RA, Peter HH (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268
Hammarström L, Vořechovský I, Webster D (2000) Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120:225–231
Hampe J, Frenzel H, Mirza MM, Croucher PJP, Cuthbert A, Mascheretti S, Huse K, Platzer M, Bridger S, Meyer B, Nürnberg P, Stokkers P, Krawczak M, Mathew CG, Curran M, Schreiber S (2002) Evidence for a NOD2-independent susceptibility locus for inflammatory bowel disease on chromosome 16p. Proc Natl Acad Sci USA 99:321–326
Hugot J-P, Chamaillard M, Zouali H, Lesage S, Cézard J-P, Belaiche J, Allmer S, Tysk C, O’Morain CA, Gassull M, Binder V, Finkel Y, Cortot A, Modigliani R, Laurent-Puig P, Gower-Rousseau C, Macry J, Colombel J-F, Sahbatou M, Thomas G (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603
Ishizaka A, Nakanishi M, Yamada S, Sakiyama Y, Matsumoto S (1989) Development of hypogammaglobulinaemia in a patient with common variable immunodeficiency. Eur J Pediatr 149:175–176
IUIS (1999) Primary immunodeficiency diseases. Report of an IUIS Scientific Committee. International Union of Immunological Societies. Clin Exp Immunol 118(Suppl 1):1–28
Johnson ML, Keeton LG, Zhu ZB, Volanakis JE, Cooper MD, Schroeder HW Jr (1997) Age-related changes in serum immunoglobulins in patients with familial IgA deficiency and common variable immunodeficiency (CVID). Clin Exp Immunol 108:477–483
Kruglyak L, Lander ES (1998) Faster multipoint linkage analysis using Fourier transforms. J Comp Biol 5:1–7
Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am J Hum Genet 58:1347–1363
Lathrop GM, Lalouel J-M, Julier C, Ott J (1984) Strategies for multilocus analysis in humans. Proc Nat Acad Sci USA 81:3443–3446
Morra M, Silander O, Calpe S, Choi M, Oettgen H, Myers L, Etzioni A, Buckley R, Terhorst C (2001) Alterations of the X-linked lymphoproliferative disease gene SH2D1A in common variable immunodeficiency syndrome. Blood 98:1321–1325
Nistala K, Gilmour KC, Cranston T, Davies EG, Goldblatt D, Gaspar HB, Jones AM (2001) X-linked lymphoproliferative disease: three atypical cases. Clin Exp Immunol 126:126–130
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar J-P, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606
Olerup O, Smith CIE, Hammarström L (1990) Different amino acids at position 57 of the HLA-DQ beta chain associated with susceptibility and resistance to IgA deficiency. Nature 347:289–290
Olerup O, Smith CI, Bjorkänder J, Hammarström L (1992) Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. Proc Natl Acad Sci USA 89:10653–10657
Ott J (1989) Computer-simulation methods in human linkage analysis. Proc Natl Acad Sci USA 86:4175–4178
Ott J (1991) Analysis of human genetic linkage, Revised edn. Johns Hopkins University Press, Baltimore, MD
Saffran DC, Parolin O, Fitch-Hilgenberg ME, Rawlings DJ, Afar DEH, Witte ON, Conley ME (1994) A point mutation in the SH2 domain of Bruton’s tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med 330:1488–1491
Salzer U, Chapel HM, Webster ADB, Pan-Hammarström Q, Schmidt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schäffer AA, Hammaström L, Grimbacher B (2005) Mutations in TNFRSF13B, which encodes TACI, are associated with common variable immunodeficiency in humans. Nat Genet 37:820–828
Schaffer FM, Palermos J, Zhu ZB, Barger BO, Cooper MD, Volanakis JE (1989) Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes. Proc Natl Acad Sci USA 86:8015–8019
Schäffer AA, Gupta SK, Shriram K, Cottingham RW Jr (1994) Avoiding recomputation in linkage analysis. Hum Hered 44:225–237
Schroeder HW Jr, Zhu ZB, March RE, Campbell RD, Berney SM, Nedospasov SA, Turetskaya RL, Atkinson TP, Go RC, Cooper MD, Volanakis JE (1998) Susceptibility locus for IgA deficiency and common variable immunodeficiency in the HLA-DR3, -B8, -A1 haplotypes. Mol Med 4:72–86
Smith CIE, Islam KB, Vořechovský I, Olerup O, Wallin E, Rabbani H, Baskin B, Hammarström L (1994) X-linked agammaglobulinemia and other immunoglobulin deficiencies. Immunol Rev 138:159–183
Terwilliger JD (1995) A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am J Hum Genet 56:777–787
Volanakis JE, Zhu ZB, Schaffer FM, Macon KJ, Palermos J, Barger BO, Go R, Campbell RD, Schroeder HW Jr, Cooper MD (1992) Major histocompatibility complex class III genes and susceptibility to immunoglobulin A deficiency and common variable immunodeficiency. J Clin Invest 89:1914–1922
Vořechovský I, Zetterquist H, Paganelli R, Koskinen S, Webster ADB, Bjorkänder J, Smith CIE, Hammarström L (1995) Family and linkage study of selective IgA deficiency and common variable immunodeficiency. Clin Immunol Immunopathol 77:185–192
Vořechovský I, Webster ADB, Plebani A, Hammarström L (1999) Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition. Am J Hum Genet 64:1096–1109
Vořechovský I, Cullen M, Carrington M, Hammarström L, Webster ADB (2000) Fine mapping of IGAD1 in IgA deficiency and common variable immunodeficiency: identification and characterization of haplotypes shared by affected members of 101 multiple-case families. J Immunology 164:4408–4416
Warnatz K et al (2004) Finally Found: human BAFF-R deficiency causes CVID. The XIth meeting of the European Society for Immunodeficiency, Versailles (Abstract #B27)
Weeks DE, Ott J, Lathrop GM (1990) SLINK: a general simulation program for linkage analysis. Am J Hum Genet 47:A204
van Zelm MC et al (2004) Novel humoral immunodeficiency caused by a CD19 defect. The XIth Meeting of the European Society for Immunodeficiency, Versailles (Abstract #B27)
Acknowledgements
We thank the families and their physicians for their participation in this research study supported by the Intramural Research Program at the National Institutes of Health, by grant SFB620-C2 from the Deutsche Forschungsgemeinschaft, by a grant from the Swedish research council, and by EU-Project QLRT-2001-01536 (IMPAD).
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Schäffer, A.A., Pfannstiel, J., Webster, A.D.B. et al. Analysis of families with common variable immunodeficiency (CVID) and IgA deficiency suggests linkage of CVID to chromosome 16q. Hum Genet 118, 725–729 (2006). https://doi.org/10.1007/s00439-005-0101-1
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DOI: https://doi.org/10.1007/s00439-005-0101-1