Advertisement

Journal of Clinical Immunology

, Volume 27, Issue 4, pp 455–459 | Cite as

Clinical Follow-Up of 11 Argentinian CD40L-Deficient Patients with 7 Unique Mutations Including the So-Called “Milder” Mutants

  • SILVIA DANIELIAN
  • MATIAS OLEASTRO
  • MARIA EVA RIVAS
  • CLAUDIO CANTISANO
  • MARTA ZELAZKO
Article

CD40 ligand (CD40L) deficiency is an X-linked combined immunodeficiency characterized by impaired class switch recombination. We analyzed clinical and molecular findings in 11 Argentinian patients from seven unrelated families. The mean age at onset of symptoms was 1.1 years (0.5–3.0 years) and the 10 alive patients have a median age of 17 years. We identified two nonsense mutations, including R11X reported as a “hypomorphic” defect, four missense mutations, and one point deletion. Although R11X was associated herein with parvovirus B19-anemia and higher Igs levels as previously described, histoplasmosis and Pneumocystis jiroveci pneumonia were also present. Other so-called “milder” mutation, T254M, was present in three related patients clinically and immunologically undistinguishable from the rest of the cohort. Furthermore, 10 of the 11 patients, having heterogeneous mutations, never had persistent neutropenia, none presented Cryptosporidium sp. infection nor developed liver-biliary tract disease, highlighting the debatable concept of “milder” mutations.

KEY WORDS:

CD40 ligand X-linked hyper IgM immunodeficiency Mutation analysis 

Notes

ACKNOWLEDGMENTS

The technical expertise of Emma Prieto is gratefully acknowledged.

REFERENCES

  1. 1.
    Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, Ugazio AG, Notarangelo LD, Levinsky RJ, Kroczek RA: Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 361:539–541, 1993PubMedCrossRefGoogle Scholar
  2. 2.
    Di Santo JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G: CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. Nature 361:541–543, 1993CrossRefGoogle Scholar
  3. 3.
    Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M, Roberts RL, Noelle RJ, Ledbetter JA, Francke U, Ochs HD: The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM Syndrome. Cell 72:291–300, 1993PubMedCrossRefGoogle Scholar
  4. 4.
    Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, Bedell MA, Edelhoff S, Disteche CM, Simoneaux DK, Fanslow WC, Belmont JW, Spriggs MK: CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259:990–993, 1993PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, Avanzini MA, Marconi M, Badolato R, Ugazio AG, Levy Y, Catalan N, Durandy A, Tbakhi A, Notarangelo LD, Plebani A: Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci USA 98:12614–12619, 2001PubMedCrossRefGoogle Scholar
  6. 6.
    Notarangelo LD, Lanzi G, Peron S, Durandy A: Defects of class-switch recombination. J Allergy Clin Immunol 117:855–864, 2006PubMedCrossRefGoogle Scholar
  7. 7.
    Conley ME, Notarangelo LD, Etzioni A: Diagnostic criteria for primary immunodeficiencies. Clin Immunol 93:190–197, 1999PubMedCrossRefGoogle Scholar
  8. 8.
    Villa A, Notarangelo LD, Di Santo JP, Macchi PP, Strina D, Frattini A, Lucchini F, Patrosso CM, Giliani S, Mantuano E, Agosti S, Nocera G, Kroczek RA, Fischer A, Ugazio AG, de Saint Basile G, Vezzoni P: Organization of the human CD40L gene: Implications for molecular defects in X chromosome-linked hyper-IgM syndrome and prenatal diagnosis. Proc Natl Acad Sci USA 91:2110–2114, 1994PubMedCrossRefGoogle Scholar
  9. 9.
    Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD: Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood 92:2421–2434, 1998PubMedGoogle Scholar
  10. 10.
    Blaeser F, Kelly M, Siegrist K, Storch GA, Buller RS, Whitlock J, Truong N, Chatila TA: Critical function of the CD40 pathway in parvovirus B19 infection revealed by a hypomorphic CD40 ligand mutation. Clin Immunol 117:231–237, 2005PubMedCrossRefGoogle Scholar
  11. 11.
    Lin Q, Rohrer J, Allen RC, Larché M, Greene JM, Shigeoka AO, Gatti RA, Derauf DC, Belmont JW, Conley ME: A single strand conformation polymorphism study of CD40 ligand. J Clin Invest 97:196–201, 1996PubMedCrossRefGoogle Scholar
  12. 12.
    Katz F, Hinshelwood S, Rutland P, Jones A, Kinnon C, Morgan G: Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome. Hum Mutat 8:223–228, 1996PubMedCrossRefGoogle Scholar
  13. 13.
    Nonoyama S, Shimadzu M, Toru H, Seyama K, Nunoi H, Neubauer M, Yata J, Ochs HD: Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome. Hum Genet 99:624–627, 1997PubMedCrossRefGoogle Scholar
  14. 14.
    Garber E, Su L, Ehrenfels B, Karpusas M, Hsu Y-M: CD154 variants associated with hyper-IgM syndrome can form oligomers and trigger CD40-mediated signals. J Biol Chem 274:33545–33550, 1999PubMedCrossRefGoogle Scholar
  15. 15.
    Ziegner UHM, Kobayashi RH, Cunningham-Rundles C, Español T, Fasth A, Huttenlocker A, Krogstad P, Marthinsen L, Notarangelo LD, Pasic S, Rieger CHL, Rudge P, Sankar R, Shigeoka AO, Stiehm ER, Sullivan KE, Webster AD, Ochs HD: Progressive neurodegeneration in patients with primary immunodeficiency disease on IVIG treatment. Clin Immunol 102:19–24, 2002PubMedCrossRefGoogle Scholar
  16. 16.
    Levy J, Español-Boren T, Thomas C, Fischer A, Tobo P, Bordigoni P, Resnick I, Fasth A, Baer M, Gómez L, Sandera EA, Tabone M-D, Plantaz D, Etzioni A, Monafo V, Abinum M, Hammarstrom L, Abrahamsen T, Jones A, Finn A, Klemola T, DeVries E, Sanal O, Peitsch MC, Notarangelo LD: Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr 131:47–54, 1997PubMedCrossRefGoogle Scholar
  17. 17.
    Winkelstein JA, Marino MC, Ochs HD, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME: The X-linked hyper-IgM syndrome. Medicine 82:373–384, 2003PubMedCrossRefGoogle Scholar
  18. 18.
    Lee W-I, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD: Molecular analysis of a large cohort of patients with the hyper IgM syndrome (HIGM). Blood 105:1881–1890, 2005PubMedCrossRefGoogle Scholar
  19. 19.
    de Vries E, Noordzij JG, Davies EG, Hartwig N, Breuning MH, Van Dongen JJM, Van Tol MJD: The 782C->T (T254M) XHIM mutation: Lack of a tight phenotype–genotype relationship. Blood 94:1488–1490, 1999PubMedGoogle Scholar
  20. 20.
    Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A: DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822–829, 2002PubMedCrossRefGoogle Scholar
  21. 21.
    den Dunnen JT, Antonarakis SE: Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion. Hum Mutat 15:7–12, 2000PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • SILVIA DANIELIAN
    • 1
    • 4
  • MATIAS OLEASTRO
    • 1
  • MARIA EVA RIVAS
    • 2
  • CLAUDIO CANTISANO
    • 3
  • MARTA ZELAZKO
    • 1
  1. 1.Immunology UnitHospital de Pediatría “Juan P Garrahan”Buenos AiresArgentina
  2. 2.Hospital de Niños “Ricardo Gutiérrez”Buenos AiresArgentina
  3. 3.Hospital “Pedro de Elizalde”Buenos AiresArgentina
  4. 4.Immunology UnitHospital de Pediatría “Juan P Garrahan”Buenos AiresArgentina

Personalised recommendations