Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1995 Apr;56(4):898–906.

Characterization of Nine Novel Mutations in the CD40 Ligand Gene in Patients with X-Linked Hyper IgM Syndrome of Various Ancestry

Paolo Macchi, Anna Villa, Dario Strina, Maria Grazia Sacco, Federica Morali, Duilio Brugnoni, Silvia Giliani, Elide Mantuano, Anders Fasth, Bengt Andersson, Ben J M Zegers, Giovanni Cavagni, Igor Reznick, Jacov Levy, Israel Zan-Bar, Yael Porat, Paolo Airò, Alessandro Plebani, Paolo Vezzoni, Luigi D Notarangelo
PMCID: PMC1801196  PMID: 7717401

Abstract

X-linked immunodeficiency with hyper-IgM (HIGMX-1) is a rare disorder caused by defective expression of the CD40 ligand (CD40L) by activated T lymphocytes, resulting in inefficient T-B cell cooperation and failure of B cells to undergo immunoglobulin isotype switch. In the present work, we describe nine patients of various ancestry who bear different mutations in the X chromosome–specific CD40L gene. Two of the mutations were nonsense mutations, one each resulting in premature stop codons at amino acid residues 39 and 140. Three patients had single point missense mutations, one each at codons 126, 140, and 144. Another patient had a 4-bp genomic deletion in exon 2, resulting in a frameshift and premature termination. Three patients showed insertions, one each of 1, 2, and 4 nt, probably because of polymerase slippage, resulting in frameshift mutation and premature termination. Overall, these observations confirm the heterogeneity of mutations in HIGMX-1. However, the identification of two patients whose mutation involves codon 140 (previously shown to be altered in two other unrelated subjects) suggests that this may be a hotspot of mutation in HIGMX-1. In two additional patients with clinical and immunological features indistinguishable from canonical HIGMX-1, no mutation was detected in the coding sequence, in the 5' flanking region, or in the 3' UTR.

Full text

PDF
898

Images in this article

903Figure 3
on p.903
903Figure 4
on p.903
904Figure 5
on p.904

Selected References

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

  1. Allen R. C., Armitage R. J., Conley M. E., Rosenblatt H., Jenkins N. A., Copeland N. G., Bedell M. A., Edelhoff S., Disteche C. M., Simoneaux D. K. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993 Feb 12;259(5097):990–993. doi: 10.1126/science.7679801. [DOI] [PubMed] [Google Scholar]
  2. Aruffo A., Farrington M., Hollenbaugh D., Li X., Milatovich A., Nonoyama S., Bajorath J., Grosmaire L. S., Stenkamp R., Neubauer M. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291–300. doi: 10.1016/0092-8674(93)90668-g. [DOI] [PubMed] [Google Scholar]
  3. Banchereau J., Bazan F., Blanchard D., Brière F., Galizzi J. P., van Kooten C., Liu Y. J., Rousset F., Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881–922. doi: 10.1146/annurev.iy.12.040194.004313. [DOI] [PubMed] [Google Scholar]
  4. DiSanto J. P., Bonnefoy J. Y., Gauchat J. F., Fischer A., de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541–543. doi: 10.1038/361541a0. [DOI] [PubMed] [Google Scholar]
  5. DiSanto J. P., Markiewicz S., Gauchat J. F., Bonnefoy J. Y., Fischer A., de Saint Basile G. Brief report: prenatal diagnosis of X-linked hyper-IgM syndrome. N Engl J Med. 1994 Apr 7;330(14):969–973. doi: 10.1056/NEJM199404073301404. [DOI] [PubMed] [Google Scholar]
  6. Farrington M., Grosmaire L. S., Nonoyama S., Fischer S. H., Hollenbaugh D., Ledbetter J. A., Noelle R. J., Aruffo A., Ochs H. D. CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1099–1103. doi: 10.1073/pnas.91.3.1099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fuleihan R., Ramesh N., Loh R., Jabara H., Rosen R. S., Chatila T., Fu S. M., Stamenkovic I., Geha R. S. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2170–2173. doi: 10.1073/pnas.90.6.2170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gauchat J. F., Aubry J. P., Mazzei G., Life P., Jomotte T., Elson G., Bonnefoy J. Y. Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production. FEBS Lett. 1993 Jan 11;315(3):259–266. doi: 10.1016/0014-5793(93)81175-y. [DOI] [PubMed] [Google Scholar]
  9. Hollenbaugh D., Grosmaire L. S., Kullas C. D., Chalupny N. J., Braesch-Andersen S., Noelle R. J., Stamenkovic I., Ledbetter J. A., Aruffo A. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992 Dec;11(12):4313–4321. doi: 10.1002/j.1460-2075.1992.tb05530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Korthäuer U., Graf D., Mages H. W., Brière F., Padayachee M., Malcolm S., Ugazio A. G., Notarangelo L. D., Levinsky R. J., Kroczek R. A. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):539–541. doi: 10.1038/361539a0. [DOI] [PubMed] [Google Scholar]
  11. Kroczek R. A., Graf D., Brugnoni D., Giliani S., Korthüer U., Ugazio A., Senger G., Mages H. W., Villa A., Notarangelo L. D. Defective expression of CD40 ligand on T cells causes "X-linked immunodeficiency with hyper-IgM (HIGM1)". Immunol Rev. 1994 Apr;138:39–59. doi: 10.1111/j.1600-065x.1994.tb00846.x. [DOI] [PubMed] [Google Scholar]
  12. Notarangelo L. D., Duse M., Ugazio A. G. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101–121. [PubMed] [Google Scholar]
  13. Pilia G., Porta G., Padayachee M., Malcolm S., Zucchi I., Villa A., Macchi P., Vezzoni P., Schlessinger D. Human CD40L gene maps between DXS144E and DXS300 in Xq26. Genomics. 1994 Jul 1;22(1):249–251. doi: 10.1006/geno.1994.1378. [DOI] [PubMed] [Google Scholar]
  14. Ramesh N., Fuleihan R., Geha R. Molecular pathology of X-linked immunoglobulin deficiency with normal or elevated IgM (HIGMX-1). Immunol Rev. 1994 Apr;138:87–104. doi: 10.1111/j.1600-065x.1994.tb00848.x. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Villa A., Notarangelo L. D., Di Santo J. P., Macchi P. P., Strina D., Frattini A., Lucchini F., Patrosso C. M., Giliani S., Mantuano E. Organization of the human CD40L gene: implications for molecular defects in X chromosome-linked hyper-IgM syndrome and prenatal diagnosis. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2110–2114. doi: 10.1073/pnas.91.6.2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Villa A., Strina D., Macchi P., Patrosso M. C., Vezzoni P., Tovo P. A., Giliani S., Ugazio A. G., Notarangelo L. D. C to T mutation causing premature termination of CD40 ligand at amino acid 221 in a patient affected by hyper IgM syndrome. Hum Mutat. 1994;3(1):73–75. doi: 10.1002/humu.1380030115. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES