Mutation of IGFBP7 causes upregulation of BRAF/MEK/ERK pathway and familial retinal arterial macroaneurysms

Am J Hum Genet. 2011 Aug 12;89(2):313-9. doi: 10.1016/j.ajhg.2011.07.010.


Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aneurysm / genetics*
  • Aneurysm / pathology
  • Base Sequence
  • Child
  • Child, Preschool
  • Extracellular Signal-Regulated MAP Kinases / genetics*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Family
  • Female
  • Humans
  • Insulin-Like Growth Factor Binding Proteins / genetics*
  • MAP Kinase Signaling System / genetics
  • Male
  • Mitogen-Activated Protein Kinase Kinases / genetics*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • Proto-Oncogene Proteins B-raf / genetics*
  • RNA Splicing / genetics
  • Retinal Artery / enzymology
  • Retinal Artery / pathology*
  • Up-Regulation / genetics
  • Young Adult


  • Insulin-Like Growth Factor Binding Proteins
  • insulin-like growth factor binding protein-related protein 1
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases