A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome
A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome
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DOI：
10.1016/j.ajhg.2015.07.009
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发表时间：
2015-09-03
影响因子：
9.8
通讯作者：
Biesecker, Leslie G.
中科院分区：
文献类型：
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作者：
Johnston, Jennifer J.;Sanchez-Contreras, Monica Y.;Biesecker, Leslie G.
Penttinen 综合征是一种独特的疾病，其特征是过早衰老，伴有脂肪萎缩、表皮和真皮萎缩，以及类似疤痕的肥厚性病变、头发稀疏、突眼、颧骨发育不全和明显的肢端骨质溶解。所有个体都是单纯病例。对受影响个体的外显子组测序发现了 PDGFRB 中的从头 c.1994T>C p.Va1665Ala 变体，该变体编码血小板衍生生长因子受体 P。另外三个患有这种疾病的无关个体也显示出在 PDGFRB 中具有相同的变体。 PDGFRB 的独特突变已被证明可导致婴儿肌纤维瘤病、特发性基底神经节钙化以及伴有畸形面容和精神病的过度生长性疾病，这些都与 Penttinen 综合征的临床表现不重叠。我们通过将突变型和野生型 cDNA 转染到 HeLa 细胞中，评估了这种致病变异对 PDGFRB 信号通路的功能影响，转染通过 STAT3 和 PLCy 显示了配体独立的组成型信号传导。 Penttinen 综合征是一种临床上独特的遗传性疾病，由 PDGFRB 功能获得性突变引起，该突变与受体功能的特定且不寻常的扰动相关。
Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Va1665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor P. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. Distinct mutations in PDGFRB have been shown to cause infantile myofibromatosis, idiopathic basal ganglia calcification, and an overgrowth disorder with dysmorphic facies and psychosis, none of which overlaps with the clinical findings in Penttinen syndrome. We evaluated the functional consequence of this causative variant on the PDGFRB signaling pathway by transfecting mutant and wild-type cDNA into HeLa cells, and transfection showed ligand-independent constitutive signaling through STAT3 and PLCy. Penttinen syndrome is a clinically distinct genetic condition caused by a PDGFRB gain-of-function mutation that is associated with a specific and unusual perturbation of receptor function.