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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish
Pages (from-to)898-906
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 1 Jan 1995
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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