A Mutation in VWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia.
A Mutation in VWA1, Encoding von Willebrand Factor A Domain-Containing Protein 1, Is Associated With Hemifacial Microsomia.
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DOI：
10.3389/fcell.2020.571004
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发表时间：
2020
影响因子：
5.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Wang Y;Ping L;Luan X;Chen Y;Fan X;Li L;Liu Y;Wang P;Zhang S;Zhang B;Chen X
半面侏儒症（HFM）是一种罕见的先天性综合征，由第一和第二咽弓发育障碍引起，每5,600名活产婴儿中就有一名发生。我们对这种综合征的致病基因的认识存在重大差距。全外显子组测序（WES）进行了五个病人，一个无症状携带者，和两个结婚的成员的五代系谱。使用Phyre 2门户网站预测WARP（VWA 1的产物）的结构。使用吗啉代和CRISPR/Cas9技术在斑马鱼中进行原位杂交和vwa 1-敲低/敲除研究。进行Carbohydrate染色和免疫荧光。通过WES和一系列筛选，我们在一个新的候选致病基因VWA 1中鉴定了一个c.G905A：p.R302Q点突变。Phyre 2门户网站预测了WARP二级和三级结构的改变，表明其功能也发生了变化。在颅面发育相关的五个途径中的蛋白质-蛋白质相互作用的预测揭示了可能与FGF途径中的四种蛋白质的相互作用。斑马鱼的敲除/敲除研究显示咽软骨畸形。吗啡组的颅神经嵴细胞（CNCCs）增殖能力下降，咽软骨细胞结构发生改变。我们的数据表明，VWA 1的突变在功能上与HFM通过抑制CNCC增殖和破坏咽软骨细胞的组织。
Hemifacial microsomia (HFM) is a type of rare congenital syndrome caused by developmental disorders of the first and second pharyngeal arches that occurs in one out of 5,600 live births. There are significant gaps in our knowledge of the pathogenic genes underlying this syndrome. Whole exome sequencing (WES) was performed on five patients, one asymptomatic carrier, and two marry-in members of a five-generation pedigree. Structure of WARP (product of VWA1) was predicted using the Phyre2 web portal. In situ hybridization and vwa1-knockdown/knockout studies in zebrafish using morpholino and CRISPR/Cas9 techniques were performed. Cartilage staining and immunofluorescence were carried out. Through WES and a set of filtration, we identified a c.G905A:p.R302Q point mutation in a novel candidate pathogenic gene, VWA1. The Phyre2 web portal predicted alterations in secondary and tertiary structures of WARP, indicating changes in its function as well. Predictions of protein-to-protein interactions in five pathways related to craniofacial development revealed possible interactions with four proteins in the FGF pathway. Knockdown/knockout studies of the zebrafish revealed deformities of pharyngeal cartilage. A decrease of the proliferation of cranial neural crest cells (CNCCs) and alteration of the structure of pharyngeal chondrocytes were observed in the morphants as well. Our data suggest that a mutation in VWA1 is functionally linked to HFM through suppression of CNCC proliferation and disruption of the organization of pharyngeal chondrocytes.
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影响因子：
2.9
作者：
Huang, Yuanpeng J.;Mao, Binchen;Aramini, James M.;Montelione, Gaetano T.
通讯作者：
Montelione, Gaetano T.
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ
影响因子：
3.6
作者：
Grabb, W C
通讯作者：
Grabb, W C
影响因子：
2.7
作者：
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通讯作者：
Chung, BC
影响因子：
4.6
作者：
Kim, Yong-Il;Lee, Joon No;Park, Raekil
通讯作者：
Park, Raekil