Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children.
Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children.
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纯合GDF2废话突变导致循环BMP9和BMP10损失，并且与儿童中的PAH或“ HHT样”综合征有关。
DOI：
10.1002/mgg3.1685
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发表时间：
2021-12
影响因子：
2
通讯作者：
Upton PD
中科院分区：
文献类型：
--
作者：
Hodgson J;Ruiz-Llorente L;McDonald J;Quarrell O;Ugonna K;Bentham J;Mason R;Martin J;Moore D;Bergstrom K;Bayrak-Toydemir P;Wooderchak-Donahue W;Morrell NW;Condliffe R;Bernabeu C;Upton PD
内皮细胞BMP 9/10信号传导的中断可能导致遗传性出血性毛细血管扩张症（HHT）和肺动脉高压（PAH）的病理生理学，但在极罕见的纯合GDF 2（BMP 9基因）无义突变个体中，尚未证实循环BMP 9的丢失。我们研究了两名GDF 2（BMP 9基因）无义突变纯合子的儿科患者：一名患有PAH（c. [76C>T];[76C>T]或p. [Gln 26 Ter];[Gln 26 Ter]和患有肺动静脉畸形（PAVM; c. [835G>T];[835G>T]或p. [Glu 279 Ter];[Glu 279 Ter]）;均伴有面部毛细血管扩张。通过ELISA测定血浆样品的BMP 9和BMP 10。同时，使用内皮BRE-荧光素酶报告细胞系（HMEC 1-BRE）测定血清BMP活性。表达蛋白质以评估分泌和加工。在两个纯合子指示病例中均未检测到BMP 9和BMP 10的血浆水平，这对应于患者中血清来源的内皮BMP活性较低。在无症状杂合子p. [Glu 279 Ter]父母，但血清活性正常。虽然表达研究表明，在p. [Gln 26 Ter]突变体，这不会导致功能性BMP 9的分泌。总的来说，这些数据表明，导致循环BMP 9和BMP 10丢失的纯合GDF 2突变可引起儿科PAH和/或“HHT样”毛细血管扩张酶和PAVM。尽管迄今为止报告的患者的表现与HHT重叠，但没有一个符合HHT的Curaçao标准，并且在毛细血管扩张的位置和外观方面似乎与HHT不同，并且倾向于微小的弥漫性PAVM。超罕见的纯合GDF 2突变以前未显示会导致循环BMP 9蛋白的丢失。我们发现，来自两个不同家族的两个儿童个体中的纯合GDF 2突变导致血浆BMP 9和BMP 10的丢失，从而导致血清来源的BMP依赖性内皮信号的丢失。这两个人有不同的血管发育不良：一个患有肺动脉高压，另一个患有肺动静脉和毛细血管扩张综合征，与遗传性出血性毛细血管扩张不同，但可能被误诊为遗传性出血性毛细血管扩张。
Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra‐rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases. Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE‐luciferase reporter cell line (HMEC1‐BRE). Proteins were expressed for assessment of secretion and processing. Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum‐derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9. Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or “HHT‐like” telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs. Ultra‐rare homozygous GDF2 mutations have not previously been shown to lead to loss of circulating BMP9 protein. We show that homozygous GDF2 mutations in two pediatric individuals from two different families, lead to loss of plasma BMP9 and BMP10, resulting in a loss of serum‐derived BMP‐dependent endothelial signaling. The two individuals have different vascular dysplasias: one with pulmonary arterial hypertension and the second with a pulmonary arteriovenous and telangiectasia syndrome that is distinct from hereditary hemorrhagic telangiectasia but may be mistakenly diagnosed as hereditary hemorrhagic telangiectasia.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.6
作者：
Gräf S;Haimel M;Bleda M;Hadinnapola C;Southgate L;Li W;Hodgson J;Liu B;Salmon RM;Southwood M;Machado RD;Martin JM;Treacy CM;Yates K;Daugherty LC;Shamardina O;Whitehorn D;Holden S;Aldred M;Bogaard HJ;Church C;Coghlan G;Condliffe R;Corris PA;Danesino C;Eyries M;Gall H;Ghio S;Ghofrani HA;Gibbs JSR;Girerd B;Houweling AC;Howard L;Humbert M;Kiely DG;Kovacs G;MacKenzie Ross RV;Moledina S;Montani D;Newnham M;Olschewski A;Olschewski H;Peacock AJ;Pepke-Zaba J;Prokopenko I;Rhodes CJ;Scelsi L;Seeger W;Soubrier F;Stein DF;Suntharalingam J;Swietlik EM;Toshner MR;van Heel DA;Vonk Noordegraaf A;Waisfisz Q;Wharton J;Wort SJ;Ouwehand WH;Soranzo N;Lawrie A;Upton PD;Wilkins MR;Trembath RC;Morrell NW
通讯作者：
Morrell NW
影响因子：
3.3
作者：
Fujiwara, Maya;Yagi, Hisato;Saji, Tsutomu
通讯作者：
Saji, Tsutomu
影响因子：
24.3
作者：
Morrell, Nicholas W.;Aldred, Micheala A.;Loyd, James E.
通讯作者：
Loyd, James E.
DOI：
10.1164/rccm.201106-1130oc
发表时间：
2011-12-15
影响因子：
24.7
作者：
Drake, Kylie M.;Zygmunt, Deborah;Aldred, Micheala A.
通讯作者：
Aldred, Micheala A.