RAD51 Haploinsufficiency Causes Congenital Mirror Movements in Humans
2012
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
netrin1 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
RAD51in two families with CMM.
RAD51mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by
nonsense-mediated decay.
RAD51was 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
RAD51in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the
molecular pathwaysunderlying bimanual motor control in humans.
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