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Research on Genetic Reversion in Primary Immunondefiriency

原发性免疫缺陷的遗传逆转研究

基本信息

批准号：
18591186
负责人：
WADA Taizo
金额：
$ 2.53万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

We have identified two novel cases of genetic reversion in primary immunodeficiency including leukocyte adhesion deficiency type 1 (LAD-1) and X-linked severe combined immunodeficiency (XSCID).1) LAD-1 is an autosomal recessive disorder caused by mutations in the ITGB2 (CD18) gene, and characterized by recurrent severe infections, impaired pus formation, and defective wound healing. We describe an unusual case of severe phenotypic LAD-1 presenting somatic mosaicism. The patient is a compound heterozygote bearing two different frameshift mutations which abrogate protein expression. CD 18 expression was, however, detected in a small proportion of T cells, but was undetectable in granulocytes, monocytes, B cells, and NK cells. The T cells were not of maternal origin, lacked the paternal mutation, and showed a selective advantage in vivo. Molecular analysis using sorted CD18+ cells revealed them to be derived from a single CD84 T cell carrying T-cell receptor VB22. These findings suggest t … More hat spontaneous in vivo reversion was responsible for the somatic mosaicism in our patient. (Blood 2007)2) XSCID is caused by mutations of the common gamma chain (γc) of cytokine receptors and usually characterized by the absence of T and natural killer (NK) cells and the presence of B Cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations including erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, low serum IgG, elevated serum IgE, and the presence of activated T cells. The patient carried a splice-site mutation (IVS 1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation that was located at position +1 of the cryptic donor site activated by the IVS1+5G>A, and to result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression. (manuscript in submission)In addition to the clinical researches, we have constructed retroviral vectors expressing reversion mutations. These vectors will be used to evaluate conditions of induction of gene reversion in vitro in future experiments. Less

我们已经确定了两个新的情况下，遗传逆转的原发性免疫缺陷，包括白细胞粘附缺陷1型（LAD-1）和X-连锁严重联合免疫缺陷（XSCID）。1）LAD-1是一种常染色体隐性遗传疾病引起的ITGB 2（CD 18）基因突变，其特征是反复严重感染，受损的脓形成，和缺陷的伤口愈合。我们描述了一个不寻常的情况下，严重的表型LAD-1提出体细胞镶嵌。该患者是一个复合杂合子携带两个不同的移码突变，废除蛋白质表达。然而，在小比例的T细胞中检测到CD 18表达，但在粒细胞、单核细胞、B细胞和NK细胞中检测不到。T细胞不是母体来源的，缺乏父系突变，并在体内显示出选择性优势。使用分选的CD 18+细胞的分子分析揭示它们源自携带T细胞受体VB 22的单个CD 84 T细胞。这些发现表明， ...更多信息在我们的病人中，自发的体内逆转是导致体细胞嵌合现象的原因。（Blood 2007）2）XSCID由细胞因子受体的共同γ链（γc）突变引起，通常以T和自然杀伤（NK）细胞缺失和B细胞存在为特征。在这里，我们报告了一个非典型的情况下，XSCID提出与自体T和NK细胞和Omenn综合征样表现，包括红皮病，淋巴结病，肝脾肿大，嗜酸性粒细胞增多症，低血清IgG，血清IgE升高，并存在活化T细胞。患者携带剪接位点突变（IVS 1+5G>A），导致大部分mRNA被错误剪接，但产生少量正常剪接的转录本，导致残留γc表达和T细胞和NK细胞的发育。皮肤活检标本显示大量的回复突变T细胞浸润。发现这些T细胞具有位于由IVS 1 +5G>A激活的隐蔽供体位点的+1位置的第二位点突变，并且导致正确剪接的完全恢复。这些发现表明，XSCID的临床谱是相当广泛的，包括模仿Omenn综合征的非典型病例，并强调了回复突变嵌合体作为可变表型表达的可能原因的重要性。除了临床研究外，我们还构建了表达回复突变的逆转录病毒载体。这些载体将用于在未来的实验中评估体外诱导基因回复的条件。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Somatic revertant mosaicism in a patient with leukocyte adhesion deficiency type 1

DOI：
10.1182/blood-2006-08-039057
发表时间：
2007-02-01
期刊：
BLOOD
影响因子：
20.3
作者：
Tone, Yumi;Wada, Taizo;Yachie, Akihiro
通讯作者：
Yachie, Akihiro

Skin infiltration of CD56^<bright> CD16^<(-)>natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations

具有 Omenn 综合征样表现的 X-SCID 病例中 CD56^<bright> CD16^<(-)>自然杀伤细胞的皮肤浸润

DOI：
发表时间：
2007
期刊：
Eur J Haematol 79(1)
影响因子：
0
作者：
F. Shibata;T. Toma;T. Wada;M. Inoue;Y. Tone;K. Ohta;Y. Kasahara;Sano F;Kimura M;Ikeno M;S. Koizumi;A. Yachie
通讯作者：
A. Yachie

T細胞に遺伝子変異のreversion(復帰)を認めた白血球接着異常症の1例

T细胞基因突变逆转白细胞粘附障碍一例