Abstract
The Immunoglobulin Heavy chain Constant region (IGHC) locus is a multigene family composed of highly homologous segments often involved in unequal crossings over that lead to deleted and duplicated haplotypes. The frequencies of these haplotypes in 558 individuals from Lombardy, Veneto, Puglia and Sardinia were determined by Pulsed Field Gel Electrophoresis (PFGE), followed by Southern blotting with four IGHC probes, and compared with those observed in 110 subjects from Piedmont. Twenty deletions and 60 duplications were characterized, all in heterozygous individuals except for 2 homozygous deletions. The differences in frequency between the five populations were not significant. The deletions/duplications involved one or more genes: GP-A2, A1-E and G4 duplications, and A1-E and GP-A2 deletions were the most common. Four new duplications are described: three, involving the genes from GP to A2, from G2 to G4, and G4, are counterparts of known deletions. The fourth duplication spans from GP to G2. A G1 deleted heterozygous individual never previously described in Italy is reported. All the rearranged haplotypes seem to be the result of unequal crossing over. The difference between the number of duplications and deletions was significant in Sardinia, Lombardy, Puglia and in the total of 668 subjects (P < 0.001). This may be due to selection or genetic drift.
Similar content being viewed by others
References
Battey J, Max EE, McBride WO, Swan D, Leder P (1982) A processed human immunoglobulin E gene has moved to chromosome 9. Proc Natl Acad Sci USA 79:5956–5960
Bech-Hansen NT, Cox DW (1986) Duplication of the human immunoglobulin heavy chain gamma 2 gene. Am J Hum Genet 38:67–74
Bottaro A, DeMarchi M, DeLange GG, Boccazzi C, Caldesi F, Gallina R, Carbonara AO (1989a) New types of multiple and single gene deletions in the IGHC locus. Immunogenetics 29:44–48
Bottaro A, DeMarchi M, DeLange G, Carbonara AO (1989b) Gene deletions within the human immunoglobulin heavy chain constant region gene cluster. Exp Clin Immunogenet 6:55–59
Bottaro A, Cariota U, DeLange G, DeMarchi M, Gallina R, Vlug A, Carbonara AO (1990) Multiple levels of analysis of an IgG4 gene deletion. Hum Genet 86:191–197
Bottaro A, Cariota U, DeMarchi M, Carbonara AO (1991) Pulsed field electrophoresis screening for the Immunoglobulin Heavy Chain Constant region (IGHC) multigene deletions and duplications. Am J Hum Genet 48:745–756
Bottaro A, Gallina R, Brusco A, Cariota U, Boccazzi C, Barilaro MR, Plebani A, Ugazio AG, van Leeuwen AM, DeLange GG, Vaerman JP, Carbonara AO (1993) Familial clustering of IGHC deletions and duplications: functional and molecular analysis. Immunogenetics 37:356–363
Brusco A, Cariota U, Bottaro A, Boccazzi C, Plebani A, Ugazio AG, Galanello R, Leeuwen AM van, DeLange GG, Depelchin S, Carbonara AO (1994) Structural and immunologic analysis of gene triplications in the Ig heavy chain constant region locus. J Immunol 152:129–135
Chaabani H, Bech-Hansen NT, Cox DW (1986) A multigene deletion within the immunoglobulin heavy chain region. Am J Hum Genet 37:1164–1171
Drummond-Borg M, Deeb SS, Motulsky AG (1989) Molecular patterns of X chromosome-linked color vision genes among 134 men of European ancestry. Proc Natl Acad Sci USA 86:983–987
Engstrom PE, Norhagen GE, Bottaro A, Carbonara AO, Lefranc G, Stenitz M, Soder PO, Smith CIE, Hammarström L (1990) Subclass distribution of antigen-specific IgA antibodies in normal donors and individuals with homozygous C1 or C2 gene deletions. J Immunol 145:109–116
Flanagan JG, Rabbitts TH (1982) Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing G, E and A genes. Nature 300:709–713
Goossens M, Dozy AM, Embury SH, Zachariades Z, Hadjiminas MG, Stamatoyannopoulos G, Kan YW (1980) Triplicated αglobin loci in humans. Proc Natl Acad Sci USA 77:518–523
Hammarström L, Carbonara AO, DeMarchi M, Lefranc G, Lefranc MP, Smith CIE (1987) Generation of the antibody repertoire in individuals with multiple immunoglobulin heavy chain constant region gene deletions. Scand J Immunol 25:189–194
Hendriks RW, Tol M van, DeLange GG, Shuurman RK (1989) Inheritance of a large deletion within the human immunoglobulin heavy chain constant region gene complex and immunological implications. Scand J Immunol 2:535–541
Hofker MH, Walter MA, Cox DW (1989) Complete physical map of the human immunoglobulin heavy chain constant region gene complex. Proc Natl Acad Sci USA 86:5567–5571
Keyeux G, Lefranc G, Lefranc MP (1989) A multigene deletion in the human IGH constant region locus involves highly homologous hot spots of recombination. Genomics 5:431–441
Kirsch IR, Morton CC, Nakahara K, Leder P (1982) Human immunoglobulin heavy chain genes map to a region of translocations in malignant B lymphocytes. Science 216:301–303
Lefranc MP, Rabbitts TH (1984) Human immunoglobulin heavy chain A2 allotype determination by restriction fragment length polymorphism. Nucleic Acid Res 12:1303–1311
Lefranc MP, Lefranc G, Rabbitts TH (1982) Inherited deletion of immunoglobulin heavy chain constant region genes in normal human individuals. Nature 300:760–762
Lefranc MP, Lefranc G, DeLange GG, Out TA, Broek PJ van den, Nieuwoop J van, Radl J, Helal AN, Chaabani H, Loghem E van, Rabbitts TH (1983) Instability of the human immunoglobulin heavy chain constant region locus indicated by different inherited chromosomal deletions. Mol Biol Med 1:207–217
Maeda N, Smithies O (1986) The evolution of multigenes families: human haptoglobin genes. Annu Rev Genet 20:81–108
Migone N, Oliviero S, DeLange GG, Delacroix DL, Boschis D, Altruda F, Silengo L, DeMarchi M, Carbonara AO (1984) Multiple gene deletions in the human immunoglobulin heavy chain cluster. Proc Natl Acad Sci USA 81:5811–5815
Nakatsuji T, Charver J, Wilson JB, Lam H, Reese AL (1983) Alpha chains and gamma chains abnormal hemoglobins in new born babies. Am J Hematol 14:121–127
Nathans J, Thomas D, Hogness DS (1986) Molecular genetics of human color vision: the genes encoding blue, green and red pigments. Science 232:193–202
Olsson PG, Hofker MH, Walter MA, Smith S, Hammarström L, Smith CIE, Cox DW (1991) Ig heavy chain variable and constant region genes in common variable immunodeficiency. J Immunol 147:2540–2546
Olsson PG, Rabbani H, Hammarström L, Smith CIE (1993) Novel human immunoglobulin heavy chain constant region gene deletion haplotypes characterized by pulsed-field electrophoresis. Clin Exp Immunol 94:84–90
Plebani A, Ugazio G, Meini A, Ruggeri L, Negrini A, Albertini A, Leibovitz M, Duse M, Bottaro A, Brusco A, Cariota U, Bocazzi C, Carbonara AO (1993) Extensive deletion of immunoglobulin heavy chain constant region genes in the absence of recurrent infections: when is IgC subclass deficiency clinically relevant? Clin Immunol Immunopathol 68:46–50
Rabbani H, Bottaro A, Carbonara AO, Brusco A, Cariota U, Olsson PG, Smith CIE, Hammarström L (1993) The influence of gene duplication in the human immunoglobulin heavy chain constant locus on serum levels of immunoglobulin. Immunodeficiency Rev 4:237–241
Ravetch JV, Siebenlist U, Korsmeyer S, Waldman T, Leder P (1981) Structure of the human immunoglobulin M locus: characterization of embryonic and rearranged D and J genes. Cell 27:583–591
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning, a laboratory manual, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, USA
Smith CIE, Hammarström L, Henter JI, DeLange G (1989) Molecular and serological analysis of IgG1 deficiency caused by new forms of the constant region of the Ig H chain gene deletions. J Immunol 142:4514–4519
Smithies O, Connell GE, Dixon GH (1962) Chromosomal rearrangements and evolution of haptoglobin genes. Nature 196:232–234
Takahashi N, Ueda S, Obata M, Nikaido T, Nakai S, Honjo T (1982) Structure of human immunoglobulin gamma genes: implications for the evolution of a gene family. Cell 29:671–679
Walter MA, Chambers CA, Zimmerman B, Cox DW (1990) A multigene deletion in the immunoglobulin heavy chain region in a highly atopic individual. Hum Genet 85:643–647
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brusco, A., Cariota, U., Bottaro, A. et al. Variability of the immunoglobulin heavy chain constant region locus: a population study. Hum Genet 95, 319–326 (1995). https://doi.org/10.1007/BF00225201
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00225201