Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification
Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification
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DOI：
10.1212/wnl.0b013e31827ccf34
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发表时间：
2013-01-01
期刊：
影响因子：
9.9
通讯作者：
Campion, Dominique
中科院分区：
文献类型：
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作者：
Nicolas, Gael;Pottier, Cyril;Campion, Dominique
目的：方法：在一个3代无SLC 20 A2突变的家系中，我们对2个患病的堂兄弟姐妹进行了全外显子组测序，一旦删除，我们将其删除，以确定一个新的特发性基底节钙化（IBGC）致病基因。对dbSNP 131、HapMap Project、1000 Genomes Project和我们的内部数据库（包括72个exomes.Results：17个基因在2例患者中受到相同的未知NS/SS/I变异的影响）进行非同义编码变异、剪接受体和供体位点变异以及移码编码indel（NS/SS/I）的筛选。在对亲属进行筛查后，PDGFRB基因内的p.Leu658Pro替换仍然是该家系中与该疾病分离的唯一未知突变。这种变异被预测为高度破坏性的，在13例受影响的受试者中有13例存在，在8例无钙化的亲属中不存在。对其他19例不相关的IBGC病例的PDGFRB进行测序，使我们能够检测到PDGFRB中另一个潜在的致病性取代，p.Arg987Trp，也被预测为具有高度破坏性。PDGFRB编码的蛋白参与血管生成，并通过SLC 20 A1编码的Pi转运蛋白Pit-1调节血管平滑肌细胞无机磷（Pi）的转运。结论：PDGFRB基因突变进一步支持该生物学途径参与IBGC的病理生理过程。神经病学（R）2013;80：181-187
Objectives: To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene.Methods: In a 3-generation family with no SLC20A2 mutation, we performed whole exome sequencing in 2 affected first cousins, once removed. Nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels (NS/SS/I) were filtered against dbSNP131, the HapMap Project, 1000 Genomes Project, and our in-house database including 72 exomes.Results: Seventeen genes were affected by identical unknown NS/SS/I variations in the 2 patients. After screening the relatives, the p.Leu658Pro substitution within the PDGFRB gene remained the sole unknown mutation segregating with the disease in the family. This variation, which is predicted to be highly damaging, was present in 13 of 13 affected subjects and absent in 8 relatives without calcifications. Sequencing PDGFRB of 19 other unrelated IBGC cases allowed us to detect another potentially pathogenic substitution within PDGFRB, p.Arg987Trp, also predicted to be highly damaging. PDGFRB encodes a protein involved in angiogenesis and in the regulation of inorganic phosphate (Pi) transport in vascular smooth muscle cells via Pit-1, a Pi transporter encoded by SLC20A1.Conclusion: Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology. Neurology (R) 2013;80:181-187