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Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis.

Abstract
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.
AuthorsJohn A Martignetti, Lifeng Tian, Dong Li, Maria Celeste M Ramirez, Olga Camacho-Vanegas, Sandra Catalina Camacho, Yiran Guo, Dina J Zand, Audrey M Bernstein, Sandra K Masur, Cecilia E Kim, Frederick G Otieno, Cuiping Hou, Nada Abdel-Magid, Ben Tweddale, Denise Metry, Jean-Christophe Fournet, Eniko Papp, Elizabeth W McPherson, Carrie Zabel, Guy Vaksmann, Cyril Morisot, Brendan Keating, Patrick M Sleiman, Jeffrey A Cleveland, David B Everman, Elaine Zackai, Hakon Hakonarson
JournalAmerican journal of human genetics (Am J Hum Genet) Vol. 92 Issue 6 Pg. 1001-7 (Jun 06 2013) ISSN: 1537-6605 [Electronic] United States
PMID23731542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Chemical References
  • NOTCH3 protein, human
  • Receptor, Notch3
  • Receptors, Notch
  • Receptor, Platelet-Derived Growth Factor beta
Topics
  • Amino Acid Sequence
  • Base Sequence
  • Female
  • Genes, Dominant
  • Genetic Association Studies
  • Humans
  • Male
  • Mutation, Missense
  • Myofibromatosis (congenital, genetics)
  • Pedigree
  • Receptor, Notch3
  • Receptor, Platelet-Derived Growth Factor beta (genetics)
  • Receptors, Notch (genetics)
  • Sequence Analysis, DNA

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