Mutations in Subunits of the Activating Signal Cointegrator 1 Complex Are Associated with Prenatal Spinal Muscular Atrophy and Congenital Bone Fractures

This study identifies mutations in TRIP4 and ASCC1 genes, which encode subunits of the ASC-1 complex, as the cause of a syndrome involving prenatal spinal muscular atrophy, congenital contractures, respiratory distress and bone fractures. Researchers used autozygosity mapping and whole-exome sequencing to identify homozygous and compound heterozygous mutations in TRIP4 and ASCC1 that lead to a truncation or absence of the proteins. Experiments in zebrafish confirmed the importance of Trip4 and Ascc1 for motor neuron outgrowth and muscle development, showing that knockdown of these genes leads to swimming defects.

• 1
  Homozygous and compound heterozygous nonsense and frameshift mutations in TRIP4 and ASCC1 genes cosegregate with a disease phenotype characterized by prenatal-onset SMA and congenital bone fractures.
• 2
  Knockdown of trip4 or ascc1 in zebrafish disrupts motor neuron outgrowth and formation of myotomes and neuromuscular junctions, leading to swimming defects.
• 3
  ASCC1 mutant fibroblasts show downregulation of genes associated with neurogenesis, neuronal migration, pathfinding, and bone development.