Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations.
Cell-Dependent Pathogenic Roles of Filamin B in Different Skeletal Malformations.
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DOI：
10.1155/2022/8956636
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发表时间：
2022
影响因子：
--
通讯作者：
Xu, Chao
中科院分区：
文献类型：
--
作者：
Wu, Huixiao;Wang, Yanzhou;Chen, Xinyu;Yao, Yangyang;Zhao, Wanyi;Fang, Li;Sun, Xiaoqing;Wang, Ning;Jiang, Jie;Gao, Ling;Zhao, Jiajun;Xu, Chao
细丝蛋白B（FLNB）基因突变可导致一系列常染色体骨骼畸形，包括脊椎腕跖综合征（SCT）、Larsen综合征（LRS）、I型骨发育不全（AO 1）、III型骨发育不全（AO 3）和回飞棒发育不良（BD）。其中，LRS是温和的，而BD导致更严重的表型。然而，不同FLNB变体的临床表型差异的分子机制尚未完全确定。在这里，我们提出了两个患者患有常染色体显性LRS和常染色体隐性维生素D依赖性佝偻病IA型（VDDR-IA）。全外显子组测序揭示了FLNB中的两个新的错义变体，c.4846 A>G（p.T1616 A）和c.7022 T>G（p.I2341 R），它们分别位于细丝蛋白B的重复15和22。FLNBI 2341 R在我们的LRS患者的肌肉组织中的表达显著增加。体外研究表明，这两种突变体均导致HEK 293细胞缺乏丝状伪足，并在核周区积累突变体。我们还发现c.4846A>G（p.T1616A）和c.7022T>G（p.I2341R）以不同的方式调节软骨内成骨。c.4846A>G（p.T1616A）通过抑制SHIP 2激活AKT通路，抑制Smad 3通路，并在Saos-2和ATDC 5细胞中损害Runx 2的表达。c.7022T>G（p.I2341R）在Saos-2细胞中激活AKT和Smad 3通路，并增加Runx 2的表达，而在ATDC 5细胞中，其通过抑制SHIP 2激活AKT通路，抑制Smad 3通路，并降低Runx 2的表达。我们的研究证明了两种新的FLNB变体在两种不同的临床环境中的致病机制，并证明FLNB变体不仅可以直接导致骨骼畸形，而且还可以在其他骨骼疾病的情况下加重骨骼症状。此外，FLNB变异体差异性地影响骨骼发育，这有助于FLNB相关疾病的临床异质性。
Mutations of filamin B (FLNB) gene can lead to a spectrum of autosomal skeletal malformations including spondylocarpotarsal syndrome (SCT), Larsen syndrome (LRS), type I atelosteogenesis (AO1), type III atelosteogenesis (AO3), and boomerang dysplasia (BD). Among them, LRS is milder while BD causes a more severe phenotype. However, the molecular mechanism underlying the differences in clinical phenotypes of different FLNB variants has not been fully determined. Here, we presented two patients suffering from autosomal dominant LRS and autosomal recessive vitamin D-dependent rickets type IA (VDDR-IA). Whole-exome sequencing revealed two novel missense variants in FLNB, c.4846A>G (p.T1616A) and c.7022T>G (p.I2341R), which are located in repeat 15 and 22 of filamin B, respectively. The expression of FLNBI2341R in the muscle tissue from our LRS patient was remarkably increased. And in vitro studies showed that both variants led to a lack of filopodia and accumulation of the mutants in the perinuclear region in HEK293 cells. We also found that c.4846A>G (p.T1616A) and c.7022T>G (p.I2341R) regulated endochondral osteogenesis in different ways. c.4846A>G (p.T1616A) activated AKT pathways through inhibiting SHIP2, suppressed the Smad3 pathway, and impaired the expression of Runx2 in both Saos-2 and ATDC5 cells. c.7022T>G (p.I2341R) activated both AKT and Smad3 pathways and increased the expression of Runx2 in Saos-2 cells, while in ATDC5 cells it activated AKT pathways through inhibiting SHIP2, suppressed the Smad3 pathway, and reduced the expression of Runx2. Our study demonstrated the pathogenic mechanisms of two novel FLNB variants in two different clinical settings and proved that FLNB variants could not only directly cause skeletal malformations but also worsen skeletal symptoms in the setting of other skeletal diseases. Besides, FLNB variants differentially affect skeletal development which contributes to clinical heterogeneity of FLNB-related disorders.
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DOI：
10.1002/jbmr.2287
发表时间：
2014-12
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Chen H;Ghori-Javed FY;Rashid H;Adhami MD;Serra R;Gutierrez SE;Javed A
通讯作者：
Javed A
影响因子：
5.8
作者：
Kagawa, S;Sasaoka, T;Kobayashi, M
通讯作者：
Kobayashi, M
影响因子：
6.2
作者：
Wilson, Scott G.;Jones, Michelle R.;Prince, Richard L.
通讯作者：
Prince, Richard L.
影响因子：
30.8
作者：
Krakow, D;Robertson, SP;Cohn, DH
通讯作者：
Cohn, DH
影响因子：
3.2
作者：
Nakamura, Fumihiko;Stossel, Thomas P.;Hartwig, John H.
通讯作者：
Hartwig, John H.