title: Characterization of nine novel mutations in the CD40 ligand gene in patients with X-linked hyper IgM syndrome of various ancestry.
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.
authors.affiliation: Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Richerche, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Macchi
authors.forename: A
authors.initials: A
authors.lastname: Villa
authors.forename: D
authors.initials: D
authors.lastname: Strina
authors.forename: M G
authors.initials: MG
authors.lastname: Sacco
authors.forename: F
authors.initials: F
authors.lastname: Morali
authors.forename: D
authors.initials: D
authors.lastname: Brugnoni
authors.forename: S
authors.initials: S
authors.lastname: Giliani
authors.forename: E
authors.initials: E
authors.lastname: Mantuano
authors.forename: A
authors.initials: A
authors.lastname: Fasth
authors.forename: B
authors.initials: B
authors.lastname: Andersson
mesh_terms: D001483:Base Sequence; D023201:CD40 Ligand; D008040:Genetic Linkage; D006801:Humans; D006942:Hypergammaglobulinemia / Q000235:genetics*; D007075:Immunoglobulin M; D016130:Immunophenotyping; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D013577:Syndrome; D014960:X Chromosome
chemical_list: D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D023201:CD40 Ligand