Open AccessNeuronal impact of patient-specific aberrant NRXN1α splicing
Author(s) -
Erin Flaherty,
Shaohua 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 L. Fitzgerald,
Ian Ladran,
Peter Gochman,
Judith L. Rapoport,
Nadejda M. Tsankova,
Robert E. McCullumsmith,
Gabriel E. Hoffman,
Robert Sebra,
Gang Fang,
Kristen Brennand
Publication year - 2019
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-019-0539-z
Subject(s) - gene isoform , biology , alternative splicing , mutant , phenotype , rna splicing , allele , genetics , gene , rna
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.