Neuronal impact of patient-specific aberrant NRXN1? splicing.

ABSTRACT: 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 NRXN1? alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human NRXN1? isoforms. Patient-derived NRXN1+/- hiPSC-neurons show a greater than twofold reduction in half of the wild-type NRXN1? 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 NRXN1? isoform levels as well as the presence of mutant NRXN1? isoforms.

SUBMITTER: Flaherty E 

PROVIDER: S-EPMC7451045 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature