Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis

详细信息    查看全文

• 作者：John A. Martignetti¹ ; ² ; ³ ; ¹⁷ ; ^{john.martignetti@mssm.edu} ; Lifeng Tian⁴ ; ¹⁷ ; Dong Li⁴ ; Maria Celeste M. Ramirez¹ ; Olga Camacho-Vanegas¹ ; Sandra Catalina Camacho¹ ; Yiran Guo⁴ ; Dina J. Zand⁵ ; Audrey M. Bernstein⁶ ; Sandra K. Masur⁶ ; Cecilia E. Kim⁴ ; Frederick G. Otieno⁴ ; Cuiping Hou⁴ ; Nada Abdel-Magid⁴ ; Ben Tweddale⁴ ; Denise Metry⁷ ; Jean-Christophe Fournet⁸ ; Eniko Papp⁹ ; Elizabeth W. McPherson¹⁰ ; Carrie Zabel¹⁰ ; Guy Vaksmann¹¹ ; Cyril Morisot¹¹ ; Brendan Keating⁴ ; ¹² ; ¹³ ; Patrick M. Sleiman⁴ ; ¹² ; ¹³ ; Jeffrey A. Cleveland¹⁴ ; David B. Everman¹⁵ ; Elaine Zackai¹² ; ¹³ ; Hakon Hakonarson⁴ ; ¹² ; ¹³ ; ¹⁶ ; ¹⁷ ; ^{hakonarson@email.chop.edu}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：6 June, 2013
• 年：2013
• 卷：92
• 期：6
• 页码：1001-1007
• 全文大小：917 K

文摘

Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing 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.