title: Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome.
abstract: X-linked hyper-IgM syndrome (XHIM) is a rare primary immunodeficiency caused by a defective CD40 ligand. We identified mutations of the CD40 ligand gene in 13 unrelated Japanese XHIM patients. Of the four patients with missense mutations, one had a mutation within the transmembrane domain, and the three others had mutations affecting the TNF homology region of the extracellular domain. Two of the missense mutations resulted in the substitution of amino acids that are highly conserved in TNF family proteins. Three patients had nonsense mutations, all of which resulted in the truncation of the TNF homology domain of the CD40 ligand. Three patients had genomic DNA deletions of 2, 3 or 4 nucleotides, respectively. All of the deletions were flanked by direct repeat sequences, suggesting that these deletions were caused by slipped mispairing. Three patients had mutations within introns resulting in altered splicing, and multiple splicing products were found in one patient. Thus, each of the 13 Japanese patients had different mutations, 9 of them being novel mutations. These results indicate that mutations in XHIM are highly heterogeneous, although codon 140 seems to be a hot spot of the CD40 ligand gene since two additional point mutations were located at Trp 140, bringing the total numbers of mutations affecting codon 140 to six. In one XHIM family with a missense mutation, prenatal diagnosis was performed by single-strand conformation polymorphism analysis of genomic DNA of a male fetus.
authors.affiliation: Department of Pediatrics, University of Washington, Seatle 98195, USA.
authors.forename: S
authors.initials: S
authors.lastname: Nonoyama
authors.forename: M
authors.initials: M
authors.lastname: Shimadzu
authors.forename: H
authors.initials: H
authors.lastname: Toru
authors.forename: K
authors.initials: K
authors.lastname: Seyama
authors.forename: H
authors.initials: H
authors.lastname: Nunoi
authors.forename: M
authors.initials: M
authors.lastname: Neubauer
authors.forename: J
authors.initials: J
authors.lastname: Yata
authors.forename: H D
authors.initials: HD
authors.lastname: Och
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D019013:CD40 Antigens; D023201:CD40 Ligand; D003062:Codon; D017124:Conserved Sequence; D004251:DNA Transposable Elements; D005091:Exons; D006801:Humans; D006942:Hypergammaglobulinemia / Q000097:blood / Q000235:genetics* / Q000276:immunology; D007070:Immunoglobulin A / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood*; D007564:Japan; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011296:Prenatal Diagnosis; D017384:Sequence Deletion; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry; D014960:X Chromosome
chemical_list: D019013:CD40 Antigens; D003062:Codon; D004251:DNA Transposable Elements; D007070:Immunoglobulin A; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand