Mutations of the CD40 ligand gene in 13 Japanese patients with X-linked hyper-IgM syndrome |
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Authors: | Shigeaki Nonoyama Mitsunobu Shimadzu Hano Toru Kuniaki Seyama Hiroyuki Nunoi Michael Neubauer Jun-ichi Yata Hans D Ochs |
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Institution: | (1) Department of Pediatrics, University of Washington, Seattle, WA 98195, USA, US;(2) Department of Genetics, Mitsubishi Kagaku Bio-Clinical Laboratories, Inc., Tokyo 174, Japan, JP;(3) The Institute of Medical Science, The University of Tokyo, Tokyo 108, Japan, JP;(4) Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121, USA, US;(5) Department of Pediatrics, School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113, Japan Tel.: +81-3-5803-5248; Fax: +81-3-5803-5247, +81-3-3818-7181, JP |
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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.
Received: 20 August 1996 |
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