Department of Medicine, University of Cambridge, Cambridge, UK.
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas (CSIC), and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
Mol Genet Genomic Med. 2021 Dec;9(12):e1685. doi: 10.1002/mgg3.1685. Epub 2021 Apr 9.
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.
内皮细胞 BMP9/10 信号通路的紊乱可能与遗传性出血性毛细血管扩张症（HHT）和肺动脉高压（PAH）的病理生理学有关，但尚未在携带超罕见纯合 GDF2（BMP9 基因）无义突变的个体中证实循环 BMP9 的缺失。我们研究了两名纯合 GDF2（BMP9 基因）无义突变的儿科患者：一名患有 PAH（c.[76C>T];[76C>T] 或 p.[Gln26Ter];[Gln26Ter]），另一名患有肺动静脉畸形（PAVMs；c.[835G>T];[835G>T] 或 p.[Glu279Ter];[Glu279Ter]）；两者均有面部毛细血管扩张。
通过 ELISA 测定血浆中 BMP9 和 BMP10 的含量。同时，通过内皮细胞 BRE-荧光素酶报告细胞系（HMEC1-BRE）测定血清 BMP 活性。对蛋白进行表达评估，以检测其分泌和加工情况。
两名纯合指数病例的血浆中 BMP9 和 BMP10 均无法检测到，这与患者的血清衍生内皮 BMP 活性降低相对应。无症状的杂合子 p.[Glu279Ter]父母的 BMP9 和 BMP10 水平降低，但血清活性正常。尽管表达研究表明，p.[Gln26Ter]突变可在 Met57 处起始替代翻译，但这不会导致功能性 BMP9 的分泌。
总的来说，这些数据表明，GDF2 突变导致循环 BMP9 和 BMP10 的缺失，可导致儿科 PAH 和/或“HHT 样”毛细血管扩张和 PAVMs。尽管迄今为止报道的患者的临床表现与 HHT 重叠，但没有一个符合 Curaçao HHT 标准，并且与 HHT 在毛细血管扩张的位置和外观以及微小、弥漫性 PAVMs 的倾向方面似乎有所不同。
