Neuronal impact of patient-specific aberrant NRXN1α splicing

Nat Genet. 2019 Dec;51(12):1679-1690. doi: 10.1038/s41588-019-0539-z. Epub 2019 Nov 29.


NRXN1 undergoes extensive alternative splicing, and non-recurrent heterozygous deletions in NRXN1 are strongly associated with neuropsychiatric disorders. We establish that human induced pluripotent stem cell (hiPSC)-derived neurons well represent the diversity of NRXN1α alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human NRXN1α isoforms. Patient-derived NRXN1+/- hiPSC-neurons show a greater than twofold reduction in half of the wild-type NRXN1α isoforms and express dozens of novel isoforms from the mutant allele. Reduced neuronal activity in patient-derived NRXN1+/- hiPSC-neurons is ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decrease neuronal activity levels in control hiPSC-neurons. In a genotype-dependent manner, the phenotypic impact of patient-specific NRXN1+/- mutations can occur through a reduction in wild-type NRXN1α isoform levels as well as the presence of mutant NRXN1α isoforms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • Autism Spectrum Disorder / genetics
  • Bipolar Disorder / genetics
  • Calcium-Binding Proteins / genetics*
  • Case-Control Studies
  • Depressive Disorder, Major / genetics
  • Female
  • Gene Expression
  • Heterozygote
  • Humans
  • Induced Pluripotent Stem Cells / physiology*
  • Male
  • Mice
  • Neural Cell Adhesion Molecules / genetics*
  • Protein Isoforms / genetics
  • Schizophrenia / genetics*
  • Sequence Deletion


  • Calcium-Binding Proteins
  • NRXN1 protein, human
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • Protein Isoforms