Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.
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DOI：
10.1038/s41467-018-03672-4
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发表时间：
2018-04-12
影响因子：
16.6
通讯作者：
Morrell NW
中科院分区：
文献类型：
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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
肺动脉高压（PAH）是一种罕见的疾病，预后不良。转化生长因子-β途径组分（特别是骨形态发生蛋白2型受体（BMPR 2））内的有害变异是大多数可遗传形式PAH的基础。为了确定缺失的遗传性，我们对1038例PAH指数病例和6385例PAH阴性对照受试者进行了全基因组测序。病例对照分析揭示了ATP 13 A3、AQP 1和SOX 17中罕见变异的显著过度表达，并为GDF 2在PAH中的关键作用提供了独立验证。我们证明了SOX 17和AQP 1突变与PAH的家族分离。编码BMPR 2配体的GDF 2突变导致转染细胞分泌减少。此外，我们确定了大多数以前报道的PAH基因中的致病性突变，并为进一步推定的基因提供了证据。总之，这些发现为PAH的分子基础提供了新的见解，并指出了未探索的治疗干预途径。肺动脉高压（PAH）是一种罕见的肺部疾病，其特征是小肺动脉狭窄和闭塞，最终导致右心衰竭。在这里，作者对1000多名PAH患者的全基因组进行了测序，并确定了GDF 2、ATP 13 A3、AQP 1和SOX 17中可能的致病变异。
Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention. Pulmonary arterial hypertension (PAH) is a rare lung disorder characterised by narrowing and obliteration of small pulmonary arteries ultimately leading to right heart failure. Here, the authors sequence whole genomes of over 1000 PAH patients and identify likely causal variants in GDF2, ATP13A3, AQP1 and SOX17.
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影响因子：
30.8
作者：
Eyries, Melanie;Montani, David;Soubrier, Florent
通讯作者：
Soubrier, Florent
影响因子：
2.1
作者：
Conomos MP;Miller MB;Thornton TA
通讯作者：
Thornton TA
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
9.6
作者：
Best, D. Hunter;Sumner, Kelli L.;Elliott, C. Gregory
通讯作者：
Elliott, C. Gregory
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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