Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?
复制标题
DOI：
10.1186/s13023-016-0519-7
复制
发表时间：
2016-11-05
影响因子：
3.7
通讯作者：
Boerkoel CF
中科院分区：
文献类型：
--
作者：
Morimoto M;Myung C;Beirnes K;Choi K;Asakura Y;Bokenkamp A;Bonneau D;Brugnara M;Charrow J;Colin E;Davis A;Deschenes G;Gentile M;Giordano M;Gormley AK;Govender R;Joseph M;Keller K;Lerut E;Levtchenko E;Massella L;Mayfield C;Najafian B;Parham D;Spranger J;Stenzel P;Yis U;Yu Z;Zonana J;Hendson G;Boerkoel CF
Schimke免疫-骨发育不良（SIOD）是一种多系统疾病，由SWI/ snf相关基质相关肌动蛋白依赖性染色质调节因子亚家族a样1 （SMARCAL1）基因的双等位基因突变引起。SIOD动脉硬化和t细胞免疫缺陷的基因表达变化因此，我们假设SMARCAL1缺乏通过改变肾脏基因表达导致SIOD的局灶节段性肾小球硬化（FSGS）。我们通过对SIOD患者肾脏的基因表达分析验证了这一假设，并通过对其他SIOD患者的免疫荧光分析和对果蝇的遗传相互作用分析验证了这些发现。我们发现SIOD患者肾脏中Wnt和Notch信号通路的组分和靶点表达增加，大多数SIOD患者肾脏肾小球中未磷酸化的β-catenin和Notch1细胞内结构域水平增加，果蝇SMARCAL1同源物Marcal1与Wnt和Notch信号通路基因之间存在遗传相互作用。我们得出结论，Wnt和Notch活性升高是SMARCAL1缺乏的结果，并且作为FSGS的确定原因，有助于大多数SIOD患者的肾脏疾病。这进一步阐明了SIOD的发病机制，并有望指导SIOD患者的潜在治疗方法。本文的在线版本（doi:10.1186/s13023-016-0519-7）包含补充资料，仅供授权用户使用。
Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients. The online version of this article (doi:10.1186/s13023-016-0519-7) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
10.5
作者：
Bansbach, Carol E.;Betous, Remy;Cortez, David
通讯作者：
Cortez, David
影响因子：
4.8
作者：
Postow, Lisa;Woo, Eileen M.;Funabiki, Hironori
通讯作者：
Funabiki, Hironori
影响因子：
30.8
作者：
Puel, A;Ziegler, SF;Leonard, WJ
通讯作者：
Leonard, WJ
影响因子：
3.5
作者：
Baradaran-Heravi, Alireza;Cho, Kyoung Sang;Boerkoel, Cornelius F.
通讯作者：
Boerkoel, Cornelius F.
影响因子：
3.7
作者：
Morimoto, Marie;Yu, Zhongxin;Boerkoel, Cornelius F.
通讯作者：
Boerkoel, Cornelius F.