MUTATIONS OF THE CD40 LIGAND GENE IN 13 JAPANESE PATIENTS WITH X-LINKED HYPER-IGM SYNDROME

X-linked hyper-IgM syndrome (MIM) is a rare primary immunodeficiency c aused by a defective CD40 ligand. We identified mutations of the CD40 ligand gene in 13 unrelated Japanese XHIM patients. Of the four patien ts with missense mutations, one had a mutation within the transmembran e domain, and the three others had mutations affecting the TNF homolog y region of the extracellular domain. Two of the missense mutations re sulted in the substitution of amino acids that are highly conserved in TNF family proteins. Three patients had nonsense mutations, all of wh ich resulted in the truncation of the TNF homology domain of the CD40 ligand. Three patients had genomic DNA deletions of 2, 3 or 4 nucleoti des, respectively. All of the deletions were flanked by direct repeat sequences, suggesting that these deletions were caused by slipped misp airing. Three patients had mutations within introns resulting in alter ed 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 X HIM are highly heterogeneous, although codon 140 seems to be a hot spo t of the CD40 ligand gene since two additional point mutations were lo cated at Trp 140, bringing the total numbers of mutations affecting co don 140 to six. In one XHIM family with a missense mutation, prenatal diagnosis was performed by single-strand conformation polymorphism ana lysis of genomic DNA of a male fetus.