RAD51 haploinsufficiency causes congenital mirror movements in humans

Am J Hum Genet. 2012 Feb 10;90(2):301-7. doi: 10.1016/j.ajhg.2011.12.002. Epub 2012 Feb 2.


Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axons
  • Congenital Abnormalities / genetics*
  • DCC Receptor
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Down-Regulation
  • Dyskinesias / genetics*
  • Exome / genetics
  • Family Health
  • Genetic Heterogeneity
  • Genome-Wide Association Study / methods
  • Haploinsufficiency
  • Heterozygote
  • Homologous Recombination / genetics
  • Humans
  • Motor Cortex / abnormalities
  • Movement Disorders / genetics*
  • Mutation / genetics
  • Nerve Growth Factors / genetics
  • Netrin-1
  • Pedigree
  • RNA, Messenger / genetics
  • Rad51 Recombinase / genetics*
  • Receptors, Cell Surface / genetics
  • Tumor Suppressor Proteins / genetics


  • DCC Receptor
  • DCC protein, human
  • NTN1 protein, human
  • Nerve Growth Factors
  • Ntn1 protein, mouse
  • RNA, Messenger
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • Netrin-1
  • RAD51 protein, human
  • Rad51 Recombinase