Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature.
Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature.
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杂合性复发突变导致身材矮小患者 ROR2 基因功能障碍
DOI：
10.3389/fcell.2021.661747
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wu N
中科院分区：
文献类型：
--
作者：
Gui B;Yu C;Li X;Zhao S;Zhao H;Yan Z;Cheng X;Lin J;Zheng H;Shao J;Zhao Z;Zhao L;Niu Y;Zhao Z;Wang H;Xie B;Wei X;Gui C;Li C;Chen S;Wang Y;Song Y;Gong C;Zhang TJ;Fan X;Wu Z;Chen Y;Wu N
ROR 2是ROR家族的成员，作为Wnt 5a的受体对骨骼发育至关重要。本研究的目的是调查ROR 2基因在矮小儿童中的突变谱，并确定其潜在的分子机制。我们回顾性分析了426例通过ROR 2突变筛查的矮小症患者的临床表型和全外显子组测序（WES）数据。我们随后检查了由突变引起的ROR 2蛋白表达和亚细胞位置的变化。还检查了Wnt 5a-ROR 2途径的下游信号传导分子的mRNA表达。我们在21名患者中发现了12个ROR 2突变，包括10个错义突变，1个无义突变和1个移码突变。在所有错义突变体中，通过体外实验分析了4种复发性错义突变体[c.1675G > A（p.Gly559Ser），c.2212C > T（p.Arg738Cys），c.1930G > A（p.Asp644Asn），c.2117G > A（p.Arg706Gln）]。c.1675G > A突变显著改变了ROR 2蛋白的表达和细胞定位。c.1675G > A突变也导致c-Jun的表达显著降低。相反，其他错义突变体没有对ROR 2的生物学功能产生任何破坏性影响。我们扩大了身材矮小患者ROR 2的突变谱。功能实验揭示了ROR 2基因c.1675G > A突变可能通过干扰Wnt 5a-ROR 2通路下游基因的亚细胞定位和表达而影响其表达的新的分子机制。
ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of ROR2 in children with short stature and to identify the underlying molecular mechanisms. We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2. We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a–ROR2 pathway was also examined. We identified 12 mutations in ROR2 in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments in vitro. The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2. We expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a–ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.
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影响因子：
9.8
作者：
Lammi, L;Arte, S;Nieminen, P
通讯作者：
Nieminen, P
影响因子：
9.5
作者：
Thorvaldsdóttir H;Robinson JT;Mesirov JP
通讯作者：
Mesirov JP
DOI：
10.1038/gim.2017.159
发表时间：
2018-06
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Hauer NN;Popp B;Schoeller E;Schuhmann S;Heath KE;Hisado-Oliva A;Klinger P;Kraus C;Trautmann U;Zenker M;Zweier C;Wiesener A;Abou Jamra R;Kunstmann E;Wieczorek D;Uebe S;Ferrazzi F;Büttner C;Ekici AB;Rauch A;Sticht H;Dörr HG;Reis A;Thiel CT
通讯作者：
Thiel CT
影响因子：
2.1
作者：
Oishi, I;Suzuki, H;Minami, Y
通讯作者：
Minami, Y
影响因子：
3.5
作者：
Alfaro, Ivan E.;Varela-Nallar, Lorena;Inestrosa, Nibaldo C.
通讯作者：
Inestrosa, Nibaldo C.