INACTIVATION OF THE SURVIVAL MOTOR-NEURON GENE, A CANDIDATE GENE FOR HUMAN SPINAL MUSCULAR-ATROPHY, LEADS TO MASSIVE CELL-DEATH IN EARLY MOUSE EMBRYOS

Proximal spinal muscular atrophy is an autosomal recessive human disea se of spinal motor neurons leading to muscular weakness with onset pre dominantly in infancy and childhood. With an estimated heterozygote fr equency of 1/40 it is the most common monogenic disorder lethal to inf ants; milder forms represent the second most common pediatric neuromus cular disorder. Two candidate genes-survival motor neuron (SMN) and ne uronal apoptosis inhibitory protein have been identified on chromosome 5q13 by positional cloning. However, the functional impact of these g enes and the mechanism leading to a degeneration of motor neurons rema in to be defined. To analyze the role of the SMN gene product in vivo we generated SMN-deficient mice. In contrast to the human genome, whic h contains two copies, the mouse genome contains only one SMN gene. Mi ce with homozygous SMN disruption display massive cell death during ea rly embryonic development, indicating that the SMN gene product is nec essary for cellular survival and function.