Detection of Novel Mutation in Ccm3 Causes Familial Cerebral Cavernous Malformations

J Mol Neurosci. 2015 Nov;57(3):400-3. doi: 10.1007/s12031-015-0606-6. Epub 2015 Jun 27.

Abstract

Cerebral cavernous malformations are vascular lesions that usually involve brain micro-vessels. They can occur both in a sporadic form and familial one. Causes of familial forms are mutations at three loci: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. Here, we describe a novel CCM3 missense mutation (c.422T>G) detected in two Greek brothers showing multiple lesions at magnetic resonance imaging; to date, only the youngest is symptomatic. Bioinformatics tools showed this novel variant causes a loss of function in Pdcd10 protein due to its localization in the eighth helix and, particularly, affects Leu141, a highly conserved amino acid. Roles of Pdcd10 in angiogenesis regulation and its association with early development of cerebral cavernous malformations were also considered.

Keywords: CCM3 mutation; Familial cerebral cavernous malformations; Impaired angiogenesis; Incomplete penetrance.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Substitution
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / physiology
  • Carrier Proteins / genetics
  • Conserved Sequence
  • Gait Disorders, Neurologic / etiology
  • Hemangioma, Cavernous, Central Nervous System / complications
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Hemangioma, Cavernous, Central Nervous System / pathology
  • Humans
  • KRIT1 Protein
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Mutation, Missense*
  • Neovascularization, Physiologic / genetics
  • Pedigree
  • Point Mutation*
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / physiology
  • Vision Disorders / etiology

Substances

  • Apoptosis Regulatory Proteins
  • CCM2 protein, human
  • Carrier Proteins
  • KRIT1 Protein
  • KRIT1 protein, human
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • PDCD10 protein, human
  • Proto-Oncogene Proteins