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

We have identified two novel cases of genetic reversion in primary immunodeficiency including leukocyte adhesive 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.我们描述了一种严重的表型LAD-1表现出躯体镶嵌的不寻常情况。该患者是一种复合杂合子，带有两个不同的移状突变，可以消除蛋白质的表达。然而，CD 18的表达是在一小部分T细胞中检测到的，但在粒细胞，单核细胞，B细胞和NK细胞中无法检测到。 T细胞不是母性的，缺乏父亲突变，并且在体内显示出选择性优势。使用排序的CD18+细胞的分子分析表明，它们源自带有T细胞受体VB22的单个CD84 T细胞。这些发现表明……更多的帽子赞助商在体内恢复中是造成我们患者的躯体镶嵌的原因。（血液2007）2）XSCID是由细胞因子受体的常见γ链（γc）突变引起的，通常以T和自然杀伤（NK）细胞和B细胞的存在为特征。在这里，我们报告了一种非典型XSCID呈现自体T和NK细胞以及Omenn综合征样的表现的非典型情况。该患者携带剪接位点突变（IVS 1+5g> a），导致大多数mRNA被错误地剪接，但通常以较小的量产生剪接的转录本，从而导致残留的γC表达和T和NK细胞的发育。皮肤活检标本显示恢复T细胞的大量浸润。发现这些T细胞具有第二个位点突变，该突变位于IVS1 +5G> a激活的加密供体位置的位置+1，并导致完全恢复正确的剪接。这些发现表明，XSCID的临床光谱相当广泛，包括模仿Omenn综合征的非典型病例，并强调了恢复镶嵌物作为可变表型表达的可能原因的重要性。（提交中的手稿）除了临床研究外，我们还构建了表达反向突变的逆转录病毒载体。这些向量将用于评估未来实验中体外诱导基因恢复的条件。较少的

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

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

DOI：
10.1182/blood-2007-08-039057
发表时间：
2006-09
期刊：
Blood
影响因子：
20.3
作者：
Y. Tone;T. Wada;F. Shibata;T. Toma;Y. Hashida;Y. Kasahara;S. Koizumi;A. Yachie
通讯作者：
Y. Tone;T. Wada;F. Shibata;T. Toma;Y. Hashida;Y. Kasahara;S. Koizumi;A. Yachie

Omenn症候群様症状を呈した非典型的X-SCIDにみられた遺伝子変異のreversion

具有 Omenn 综合征样症状的非典型 X-SCID 中发现的基因突变逆转