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

Am J Hum Genet. 2016 Mar 3;98(3):473-489. doi: 10.1016/j.ajhg.2016.01.006. Epub 2016 Feb 25.


Transcriptional signal cointegrators associate with transcription factors or nuclear receptors and coregulate tissue-specific gene transcription. We report on recessive loss-of-function mutations in two genes (TRIP4 and ASCC1) that encode subunits of the nuclear activating signal cointegrator 1 (ASC-1) complex. We used autozygosity mapping and whole-exome sequencing to search for pathogenic mutations in four families. Affected individuals presented with prenatal-onset spinal muscular atrophy (SMA), multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. We identified homozygous and compound-heterozygous nonsense and frameshift TRIP4 and ASCC1 mutations that led to a truncation or the entire absence of the respective proteins and cosegregated with the disease phenotype. Trip4 and Ascc1 have identical expression patterns in 17.5-day-old mouse embryos with high expression levels in the spinal cord, brain, paraspinal ganglia, thyroid, and submandibular glands. Antisense morpholino-mediated knockdown of either trip4 or ascc1 in zebrafish disrupted the highly patterned and coordinated process of α-motoneuron outgrowth and formation of myotomes and neuromuscular junctions and led to a swimming defect in the larvae. Immunoprecipitation of the ASC-1 complex consistently copurified cysteine and glycine rich protein 1 (CSRP1), a transcriptional cofactor, which is known to be involved in spinal cord regeneration upon injury in adult zebrafish. ASCC1 mutant fibroblasts downregulated genes associated with neurogenesis, neuronal migration, and pathfinding (SERPINF1, DAB1, SEMA3D, SEMA3A), as well as with bone development (TNFRSF11B, RASSF2, STC1). Our findings indicate that the dysfunction of a transcriptional coactivator complex can result in a clinical syndrome affecting the neuromuscular system.

Keywords: ASCC1; TRIP4; arthrogryposis multiplex congenita; bone fractures; exome sequencing; neuromuscular unit; respiratory distress; spinal muscular atrophy; zebrafish model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arthrogryposis / diagnosis
  • Arthrogryposis / genetics
  • Carrier Proteins / genetics
  • Cells, Cultured
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fractures, Bone / diagnosis
  • Fractures, Bone / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Homozygote
  • Humans
  • LIM Domain Proteins / genetics
  • Mice
  • Molecular Sequence Data
  • Muscular Atrophy, Spinal / diagnosis
  • Muscular Atrophy, Spinal / genetics*
  • Mutation
  • Nuclear Proteins / genetics
  • Pedigree
  • Phenotype
  • Transcription Factors / genetics*
  • Zebrafish
  • Zebrafish Proteins / genetics


  • CSRP1 protein, human
  • Carrier Proteins
  • Csrp1 protein, mouse
  • LIM Domain Proteins
  • Nuclear Proteins
  • TRIP4 protein, human
  • Transcription Factors
  • Trip4 protein, mouse
  • Zebrafish Proteins
  • csrp1a protein, zebrafish