Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations

Am J Hum Genet. 2003 Dec;73(6):1459-64. doi: 10.1086/380314. Epub 2003 Nov 17.


Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. Mutations in the gene KRIT1 are responsible for type 1 CCM (CCM1). We report that a novel gene, MGC4607, exhibits eight different mutations in nine families with type 2 CCM (CCM2). MGC4607, similar to the KRIT1 binding partner ICAP1alpha, encodes a protein with a phosphotyrosine-binding domain. This protein may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Northern
  • Brain / embryology*
  • Central Nervous System Vascular Malformations / genetics*
  • Chromosome Mapping
  • Genetic Predisposition to Disease*
  • Humans
  • Integrins / genetics
  • Integrins / metabolism*
  • KRIT1 Protein
  • Magnetic Resonance Imaging
  • Microtubule-Associated Proteins / genetics
  • Morphogenesis
  • Mutation / genetics
  • Proto-Oncogene Proteins / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Signal Transduction*


  • Integrins
  • KRIT1 Protein
  • KRIT1 protein, human
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins