Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis
Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis
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DOI：
10.1016/j.ajhg.2013.04.024
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发表时间：
2013-06-06
影响因子：
9.8
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
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作者：
Martignetti, John A.;Tian, Lifeng;Hakonarson, Hakon
婴儿肌纤维瘤病（IM）是一种间充质细胞增生的疾病，其特征是在皮肤、肌肉、骨骼和内脏中发生非转移性肿瘤。在多代家庭中发生提示常染色体显性（AD）遗传模式，但也提出了常染色体隐性（AR）遗传模式。我们进行了全外显子组测序（WES）在9个不相关的家庭成员临床诊断为AD IM，以确定该疾病的遗传起源。在8个家族中，我们确定了PDGFRB中两种致病突变之一，c.1978C>A（p.Pro660Thr）和c.1681C>T（p.Arg561Cys）。有趣的是，一个家族没有这些PDGFRB突变中的任何一种，但所有受影响的个体都有NOTCH3中的c.4556T>C（p.Leu1519Pro）突变。我们的研究表明，PDGFRB突变是IM的原因，并强调NOTCH 3作为候选基因。进一步研究PDGFRB和NOTCH通路之间的串扰可能为识别导致IM的其他基因突变提供新的机会，并且是理解肿瘤生长和消退及其靶向治疗机制的必要的第一步。
Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonrnetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal-recessive (AR) modes of inheritance have also been proposed. We performed whole-exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment.