Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy
Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy
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DOI：
10.1038/nm.3046
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发表时间：
2013-02-01
期刊：
影响因子：
82.9
通讯作者：
Luis de la Pompa, Jose
中科院分区：
文献类型：
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作者：
Luxan, Guillermo;Casanova, Jesus C.;Luis de la Pompa, Jose
左心室致密化不全（LVNC）导致心室小梁突出并降低心脏收缩功能。 LVNC 的临床表现从无症状到心力衰竭不等。我们发现人类 MIB1（mindbomb 同源物 1）编码 E3 泛素连接酶，促进 NOTCH 配体 DELTA 和 JAGGED 的内吞作用，我们发现，人类 MIB1（mindbomb 同源物 1）的种系突变会导致常染色体显性谱系中的 LVNC，受影响的个体表现出 NOTCH I 活性降低和靶基因表达减少。细胞和斑马鱼胚胎的功能研究以及计算机模型表明，MIB1 作为二聚体发挥作用，但会被人类突变破坏。小鼠心肌中 Mib1 的靶向失活会导致 LVNC，这是一种通过心肌 Jagged1 或心内膜 Notch 1 失活模拟的表型。心肌 Mib1 突变体表现出心室 Notch1 活性降低、致密心肌扩张为增殖、不成熟的小梁以及心脏发育和疾病基因的异常表达。这些结果暗示 LVNC 中的 NOTCH 信号传导，并表明 MIB1 突变阻止心室心肌发育，防止小梁成熟和压缩。
Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH I activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch 1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.