PDGFB Partial Deletion: a New, Rare Mechanism Causing Brain Calcification with Leukoencephalopathy
PDGFB Partial Deletion: a New, Rare Mechanism Causing Brain Calcification with Leukoencephalopathy
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DOI：
10.1007/s12031-014-0265-z
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发表时间：
2014-06-01
影响因子：
3.1
通讯作者：
Hannequin, Didier
中科院分区：
文献类型：
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作者：
Nicolas, Gael;Rovelet-Lecrux, Anne;Hannequin, Didier
特发性基底节钙化是一种进行性脑功能障碍，具有不同的运动、认知和精神表现。它是作为常染色体显性遗传性状遗传的。在过去的2年中，已经确定了三个引起IBGC的基因：SLC 20 A2，PDGFRB和PDGFB。生物学和遗传学证据表明，SLC 20 A2或PDGFB/PDGFRB通路的功能丧失是突变患者钙化的潜在机制。最近，在一项针对SLC 20 A2的研究中，报道了该位点的大缺失。没有研究系统地搜索涉及这三个基因的拷贝数变异（CNV）。我们设计了一种多个短荧光片段（QMPSF）的定量PCR检测方法，用于在一次检测中检测涉及这三个基因之一的CNVs。在我们的IBGC病例系列的27例无SLC 20 A2、PDGFRB和PDGFB突变的无关患者中，我们在1例患者中发现了涉及PDGFB外显子2至5的杂合部分缺失。该患者表现出纹状体苍白球齿状核钙化和推测为血管起源的白色高信号，与情绪障碍、轻微认知能力下降和步态障碍相关。我们通过RT-PCR实验证实携带该缺失的等位基因被转录。所得cDNA缺乏蛋白质的几个关键功能结构域的序列。PDGFB基因内缺失是引起IBGC的一种新的和罕见的机制。应在无点突变的患者中研究涉及三种IBGC致病基因的CNV。
Idiopathic basal ganglia calcification (IBGC) is a progressive cerebral disorder with diverse motor, cognitive, and psychiatric expression. It is inherited as an autosomal dominant trait. Three IBGC-causing genes have been identified in the past 2 years: SLC20A2, PDGFRB, and PDGFB. Biological and genetic evidence showed that loss of function of either SLC20A2 or the PDGFB/PDGFRB pathway was the mechanism underlying calcification in patients with a mutation. Recently, in a study focusing on SLC20A2, a large deletion at this locus was reported. No study has systematically searched for copy number variants (CNV) involving these three genes. We designed a quantitative PCR assay of multiple short fluorescent fragments (QMPSF) to detect CNVs involving one of these three genes in a single assay. Among the 27 unrelated patients from our IBGC case series with no mutation in SLC20A2, PDGFRB, and PDGFB, we identified in one patient a heterozygous partial deletion involving exons 2 to 5 of PDGFB. This patient exhibited both strio-pallido-dentate calcification and white matter hyperintensity of presumed vascular origin, associated with mood disorder, subtle cognitive decline, and gait disorder. We confirmed by RT-PCR experiments that the allele carrying the deletion was transcribed. The resulting cDNA lacks sequence for several critical functional domains of the protein. Intragenic deletion of PDGFB is a new and rare mechanism causing IBGC. CNVs involving the three IBGC-causing genes should be investigated in patients with no point mutation.