Neuronal impact of patient-specific aberrant NRXN1α splicing

Erin Flaherty, Shijia Zhu, Natalie Barretto, Esther Cheng, P. J.Michael Deans, Michael B. Fernando, Nadine Schrode, Nancy Francoeur, Alesia Antoine, Khaled Alganem, Madeline Halpern, Gintaras Deikus, Hardik Shah, Megan Fitzgerald, Ian Ladran, Peter Gochman, Judith Rapoport, Nadejda M. Tsankova, Robert McCullumsmith, Gabriel E. HoffmanRobert Sebra, Gang Fang, Kristen J. Brennand

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1679-1690
Number of pages12
JournalNature genetics
Issue number12
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Genetics


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