ZMAT2, a newly-identified potential disease-causing gene in congenital radioulnar synostosis, modulates BMP signaling.
ZMAT2, a newly-identified potential disease-causing gene in congenital radioulnar synostosis, modulates BMP signaling.
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DOI：
10.1016/j.bone.2020.115349
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发表时间：
2020-04
期刊：
影响因子：
4.1
通讯作者：
Takako Suzuki;Masaki Nakano;Masatoshi Komatsu;J. Takahashi;H. Kato;Yukio Nakamura
中科院分区：
文献类型：
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作者：
Takako Suzuki;Masaki Nakano;Masatoshi Komatsu;J. Takahashi;H. Kato;Yukio Nakamura
先天性尺桡关节闭锁（RUS）是一种罕见的骨骼疾病，其特征是桡骨和尺骨融合。由于RUS的病因在很大程度上是未知的，其治疗方案目前有限。锌指基质- 2型（ZMAT2）基因的Ade novomissense突变在一名5岁的RUS男孩中被发现。在此，我们试图进一步探索zmat2在斑马鱼中的功能。全山原位杂交显示zZmat2在胸鳍（相当于人的上肢）和颅面区域特异表达，免疫组化显示zZmat2在胸鳍和心脏区域表达。基因敲低会导致胸鳍和背腹图案的缺陷。zzmat2敲低也会导致胚胎背化，这种表型与骨形态发生蛋白（BMP）信号传导减少或不足一致。byzbmp2bRNA过表达部分挽救了这些异常，同时过表达野生型zzmat2完全挽救了这些异常。重要的是，与新发现的突变相对应的mutantzzmat2的过表达并不能完全挽救背-腹侧模式缺陷。以上结果表明，zmat2通过BMP信号通路调控骨骼发育，其突变可能导致生物活性的丧失或降低。因此，新发现的zmat2突变可能通过解除BMP信号传导而在RUS中发挥因果作用。
Congenital radioulnar synostosis (RUS) is a rare skeletal disorder that is characterized by fusion of the radius and ulna. As the etiology of RUS is largely unknown, its treatment options are currently limited. Ade novomissense mutation in the zinc finger matrin-type 2 (ZMAT2) gene was newly identified in a 5-year-old boy with RUS using whole-exome sequencing. Herein, we sought to further explore the function ofzmat2in zebrafish. Whole-mountin situhybridization revealed site-specific expression ofzzmat2in the pectoral fins (equivalent to human upper limbs) and craniofacial regions, while immunohistochemistry showed the expression of zZmat2 in the pectoral fins and heart region. Gene knockdown produced defects in the pectoral fins and dorso-ventral patterning.zzmat2knockdown also caused embryo dorsalization, a phenotype consistent with reduced/insufficient bone morphogenetic protein (BMP) signaling. These abnormalities were partially rescued byzbmp2bRNA overexpression and fully rescued by simultaneous overexpression of wild-typezzmat2. Importantly, the overexpression of mutantzzmat2corresponding to the newly-identified mutation did not fully rescue the dorso-ventral patterning defects. The above findings indicate thatZMAT2regulates skeletal developmentviathe BMP signaling pathway, and its mutation may lead to a loss or reduction in biological activity. Thus, the newly identifiedZMAT2mutation potentially plays a causal role in RUS through deregulation of BMP signaling.