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. 1988 Oct;82(4):1244–1252. doi: 10.1172/JCI113722

Gamma heavy chain disease in man. Genomic sequence reveals two noncontiguous deletions in a single gene.

A Alexander 1, I Anicito 1, J Buxbaum 1
PMCID: PMC442675  PMID: 3139711

Abstract

A genomic clone was isolated from a human lymphoid cell line which synthesized an NH2-terminally deleted gamma 3 heavy chain disease protein. Nucleotide sequence analysis revealed a normal sequence from 310 bp 5' to the initiator ATG through the codon for VH amino acid 14. Amino acid 15 was derived from the codon for the last J4 amino acid. Thus, the clone contained a deletion of the codons for the VH region beyond amino acid 14, as well as those for the entire D region and most of the J coding region. Some sequence abnormalities were observed in the 400 bp after the deletion. Beyond this, there was excellent homology to published J and intervening sequences, including those containing the enhancer elements. The 1,200-bp switch region was abruptly interrupted by a sequence corresponding to the 3' one-third of CH1. Thus, a second deletion eliminated the acceptor splice site at the 5' end of CH1. When splicing of the primary RNA transcript occurred, the truncated VH region was joined via the J4 donor splice site to the next available acceptor site 5' to the first hinge exon. Hence, the aberrant serum protein was the product of two deletions and a splice correction as well as postsynthetic NH2-terminal proteolysis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adlersberg J. B., Franklin E. C., Frangione B. Repetitive hinge region sequences in human IgG3: isolation of an 11,000-dalton fragment. Proc Natl Acad Sci U S A. 1975 Feb;72(2):723–727. doi: 10.1073/pnas.72.2.723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adlersberg J. B., Grann V., Zucker-Franklin D., Frangione B., Franklin E. C. An unusual case of a plasma cell neoplasm with an IgG3lambda myeloma and a gamma3 heavy chain disease protein. Blood. 1978 Jan;51(1):85–96. [PubMed] [Google Scholar]
  3. Alexander A., Barritault D., Buxbaum J. Gamma heavy chain disease in man: translation and partial purification of mRNA coding for the deleted protein. Proc Natl Acad Sci U S A. 1978 Oct;75(10):4774–4778. doi: 10.1073/pnas.75.10.4774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Alexander A., Rosen S., Buxbaum J. Human immunoglobulin genes in health and disease. Clin Immunol Rev. 1985;4(1):31–94. [PubMed] [Google Scholar]
  5. Alexander A., Steinmetz M., Barritault D., Frangione B., Franklin E. C., Hood L., Buxbaum J. N. gamma Heavy chain disease in man: cDNA sequence supports partial gene deletion model. Proc Natl Acad Sci U S A. 1982 May;79(10):3260–3264. doi: 10.1073/pnas.79.10.3260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Arnaud P., Wang A. C., Gianazza E., Wang I. Y., Lasne Y., Creyssel R., Fudenberg H. H. Gamma heavy chain disease protein CHA: immunological and structural studies. Mol Immunol. 1981 May;18(5):379–384. doi: 10.1016/0161-5890(81)90099-7. [DOI] [PubMed] [Google Scholar]
  7. Bakhshi A., Guglielmi P., Siebenlist U., Ravetch J. V., Jensen J. P., Korsmeyer S. J. A DNA insertion/deletion necessitates an aberrant RNA splice accounting for a mu heavy chain disease protein. Proc Natl Acad Sci U S A. 1986 Apr;83(8):2689–2693. doi: 10.1073/pnas.83.8.2689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Benton W. D., Davis R. W. Screening lambdagt recombinant clones by hybridization to single plaques in situ. Science. 1977 Apr 8;196(4286):180–182. doi: 10.1126/science.322279. [DOI] [PubMed] [Google Scholar]
  9. Berman J. E., Mellis S. J., Pollock R., Smith C. L., Suh H., Heinke B., Kowal C., Surti U., Chess L., Cantor C. R. Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J. 1988 Mar;7(3):727–738. doi: 10.1002/j.1460-2075.1988.tb02869.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Biewenga J., Frangione B., Franklin E. C., van Loghem E. A gamma l heavy-chain disease protein *EST) lacking the entire VH and CHl domains. Scand J Immunol. 1980;11(6):601–607. doi: 10.1111/j.1365-3083.1980.tb00028.x. [DOI] [PubMed] [Google Scholar]
  11. Blin N., Stafford D. W. A general method for isolation of high molecular weight DNA from eukaryotes. Nucleic Acids Res. 1976 Sep;3(9):2303–2308. doi: 10.1093/nar/3.9.2303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Buxbaum J. N., Alexander A., Olivier O. Gamma heavy chain disease in man: synthesis of a deleted gamma3 immunoglobulin by lymphoid cells in short and long term tissue culture. Clin Exp Immunol. 1978 Jun;32(3):489–497. [PMC free article] [PubMed] [Google Scholar]
  13. Buxbaum J. N. Department of medicine - rheumatology service rheumatic diseases study group. Ric Clin Lab. 1976 Oct-Dec;6(4):301–317. [PubMed] [Google Scholar]
  14. Cazal P. La transfusion sanguine: I. l'originalité médico-sociale de la transfusion sanguine et les principes de base pour une organization nationale de transfusion sanguine. Rev Bras Pesqui Med Biol. 1975 May-Aug;8(3-4):315–325. [PubMed] [Google Scholar]
  15. Conley M. E., Bartelt M. S. In vitro regulation of IgA subclass synthesis. II. The source of IgA2 plasma cells. J Immunol. 1984 Nov;133(5):2312–2316. [PubMed] [Google Scholar]
  16. Cooper S. M., Franklin E. C., Frangione B. Molecular defect in a gamma-2 heavy chain. Science. 1972 Apr 14;176(4031):187–189. doi: 10.1126/science.176.4031.187. [DOI] [PubMed] [Google Scholar]
  17. Croce C. M., Nowell P. C. Molecular basis of human B cell neoplasia. Blood. 1985 Jan;65(1):1–7. [PubMed] [Google Scholar]
  18. Dolby T. W., Devuono J., Croce C. M. Cloning and partial nucleotide sequence of human immunoglobulin mu chain cDNA from B cells and mouse-human hybridomas. Proc Natl Acad Sci U S A. 1980 Oct;77(10):6027–6031. doi: 10.1073/pnas.77.10.6027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Falkner F. G., Zachau H. G. Correct transcription of an immunoglobulin kappa gene requires an upstream fragment containing conserved sequence elements. Nature. 1984 Jul 5;310(5972):71–74. doi: 10.1038/310071a0. [DOI] [PubMed] [Google Scholar]
  20. Frangione B. A new immunoglobulin variant: gamma3 heavy chain disease protein CHI. Proc Natl Acad Sci U S A. 1976 May;73(5):1552–1555. doi: 10.1073/pnas.73.5.1552. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Frangione B., Franklin E. C. Correlation between fragmented immunoglobulin genes and heavy chain deletion mutants. Nature. 1979 Oct 18;281(5732):600–602. doi: 10.1038/281600a0. [DOI] [PubMed] [Google Scholar]
  22. Frangione B., Franklin E. C., Smithies O. Unusual genes at the aminoterminus of human immunoglobulin variants. Nature. 1978 Jun 1;273(5661):400–401. doi: 10.1038/273400a0. [DOI] [PubMed] [Google Scholar]
  23. Frangione B., Franklin E. C. Split immunoglobulin genes and human heavy chain deletion-mutants. J Immunol. 1979 Apr;122(4):1177–1179. [PubMed] [Google Scholar]
  24. Frangione B., Lee L., Haber E., Bloch K. J. Protein Hal: partial deletion of a " " immunoglobulin gene(s) and apparent reinitiation at an internal AUG codon. Proc Natl Acad Sci U S A. 1973 Apr;70(4):1073–1077. doi: 10.1073/pnas.70.4.1073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Frangione B., Rosenwasser E., Prelli F., Franklin E. C. Primary structure of human gamma 3 immunoglobulin deletion mutant: gamma 3 heavy-chain disease protein Wis. Biochemistry. 1980 Sep 2;19(18):4304–4308. doi: 10.1021/bi00559a024. [DOI] [PubMed] [Google Scholar]
  26. Franklin E. C., Frangione B. Structural variants of human and murine immunoglobulins. Contemp Top Mol Immunol. 1975;4:89–126. doi: 10.1007/978-1-4615-8930-3_4. [DOI] [PubMed] [Google Scholar]
  27. Franklin E. C., Frangione B. The molecular defect in a protein (CRA) found in gamma-1 heavy chain disease, and its genetic implications. Proc Natl Acad Sci U S A. 1971 Jan;68(1):187–191. doi: 10.1073/pnas.68.1.187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Franklin E. C., Kyle R., Seligmann M., Frangione B. Correlation of protein structure and immunoglobulin gene organization in the light of two new deleted heavy chain disease proteins. Mol Immunol. 1979 Nov;16(11):919–921. doi: 10.1016/0161-5890(79)90090-7. [DOI] [PubMed] [Google Scholar]
  29. Franklin E. C., Prelli F., Frangione B. Human heavy chain disease protein WIS: implications for the organization of immunoglobulin genes. Proc Natl Acad Sci U S A. 1979 Jan;76(1):452–456. doi: 10.1073/pnas.76.1.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Franklin E. C. The structural heterogeneity among degraded gamma heavy chain disease proteins. J Immunol. 1978 Dec;121(6):2582–2583. [PubMed] [Google Scholar]
  31. Hayday A. C., Gillies S. D., Saito H., Wood C., Wiman K., Hayward W. S., Tonegawa S. Activation of a translocated human c-myc gene by an enhancer in the immunoglobulin heavy-chain locus. 1984 Jan 26-Feb 1Nature. 307(5949):334–340. doi: 10.1038/307334a0. [DOI] [PubMed] [Google Scholar]
  32. Hendershot L., Bole D., Köhler G., Kearney J. F. Assembly and secretion of heavy chains that do not associate posttranslationally with immunoglobulin heavy chain-binding protein. J Cell Biol. 1987 Mar;104(3):761–767. doi: 10.1083/jcb.104.3.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Huck S., Fort P., Crawford D. H., Lefranc M. P., Lefranc G. Sequence of a human immunoglobulin gamma 3 heavy chain constant region gene: comparison with the other human C gamma genes. Nucleic Acids Res. 1986 Feb 25;14(4):1779–1789. doi: 10.1093/nar/14.4.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kodaira M., Kinashi T., Umemura I., Matsuda F., Noma T., Ono Y., Honjo T. Organization and evolution of variable region genes of the human immunoglobulin heavy chain. J Mol Biol. 1986 Aug 20;190(4):529–541. doi: 10.1016/0022-2836(86)90239-1. [DOI] [PubMed] [Google Scholar]
  35. Kudo A., Ishihara T., Nishimura Y., Watanabe T. A cloned human immunoglobulin heavy chain gene with a novel direct-repeat sequence in 5' flanking region. Gene. 1985;33(2):181–189. doi: 10.1016/0378-1119(85)90092-7. [DOI] [PubMed] [Google Scholar]
  36. Kyle R. A., Greipp P. R., Banks P. M. The diverse picture of gamma heavy-chain disease. Report of seven cases and review of literature. Mayo Clin Proc. 1981 Jul;56(7):439–451. [PubMed] [Google Scholar]
  37. Messing J. New M13 vectors for cloning. Methods Enzymol. 1983;101:20–78. doi: 10.1016/0076-6879(83)01005-8. [DOI] [PubMed] [Google Scholar]
  38. Nabeshima Y., Ikenaka T. N- and C-terminal amino acid sequences of a gamma-heavy chain disease protein YOK. Immunochemistry. 1976 Mar;13(3):245–249. doi: 10.1016/0019-2791(76)90222-6. [DOI] [PubMed] [Google Scholar]
  39. Neri A., Barriga F., Knowles D. M., Magrath I. T., Dalla-Favera R. Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2748–2752. doi: 10.1073/pnas.85.8.2748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Parslow T. G., Blair D. L., Murphy W. J., Granner D. K. Structure of the 5' ends of immunoglobulin genes: a novel conserved sequence. Proc Natl Acad Sci U S A. 1984 May;81(9):2650–2654. doi: 10.1073/pnas.81.9.2650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Petrini J., Shell B., Hummel M., Dunnick W. The immunoglobulin heavy chain switch: structural features of gamma 1 recombinant switch regions. J Immunol. 1987 Mar 15;138(6):1940–1946. [PubMed] [Google Scholar]
  42. Ravetch J. V., Siebenlist U., Korsmeyer S., Waldmann T., Leder P. Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes. Cell. 1981 Dec;27(3 Pt 2):583–591. doi: 10.1016/0092-8674(81)90400-1. [DOI] [PubMed] [Google Scholar]
  43. Rose S. M., Kuehl W. M., Smith G. P. Cloned MPC 11 myeloma cells express two kappa genes: a gene for a complete light chain and a gene for a constant region polypeptide. Cell. 1977 Oct;12(2):453–462. doi: 10.1016/0092-8674(77)90121-0. [DOI] [PubMed] [Google Scholar]
  44. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schur P. H., Kyle R. A., Bloch K. J., Hammack W. J., Rivers S. L., Sargent A., Ritchie R. F., McIntyre O. R., Moloney W. C., Wolfson L. IgG subclasses: relationship to clinical aspects of multiple myeloma and frequency distribution among M-components. Scand J Haematol. 1974;12(1):60–68. doi: 10.1111/j.1600-0609.1974.tb00181.x. [DOI] [PubMed] [Google Scholar]
  46. Smith L. L., Barton B. P., Garver F. A., Chang L. S., McGuire B., Faguet G. B., Lutcher C. L. Physicochemical and immunochemical properties of gamma l heavy chain disease protein BAZ. Immunochemistry. 1978 May;15(5):323–329. doi: 10.1016/0161-5890(78)90093-7. [DOI] [PubMed] [Google Scholar]
  47. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  48. Takahashi N., Nakai S., Honjo T. Cloning of human immunoglobulin mu gene and comparison with mouse mu gene. Nucleic Acids Res. 1980 Dec 20;8(24):5983–5991. doi: 10.1093/nar/8.24.5983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Terry W. D., Ohms J. Implications of heavy chain disease protein sequences for multiple gene theories of immunoglobulin synthesis. Proc Natl Acad Sci U S A. 1970 Jun;66(2):558–563. doi: 10.1073/pnas.66.2.558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vilpo J. A., Irjala K., Viljanen M. K., Klemi P., Kouvonen I., Rönnemaa T. delta-Heavy chain disease. A study of a case. Clin Immunol Immunopathol. 1980 Dec;17(4):584–594. doi: 10.1016/0090-1229(80)90154-3. [DOI] [PubMed] [Google Scholar]
  51. Wolfenstein-Todel C., Frangione B., Prelli F., Franklin E. C. The amino acid sequence of "heavy chain disease" protein ZUC. Structure of the Fc fragment of immunoglobulin G3. Biochem Biophys Res Commun. 1976 Aug 23;71(4):907–914. doi: 10.1016/0006-291x(76)90741-5. [DOI] [PubMed] [Google Scholar]

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