TY - JOUR
T1 - Neuronal impact of patient-specific aberrant NRXN1α splicing
AU - Flaherty, Erin
AU - Zhu, Shijia
AU - Barretto, Natalie
AU - Cheng, Esther
AU - Deans, P. J.Michael
AU - Fernando, Michael B.
AU - Schrode, Nadine
AU - Francoeur, Nancy
AU - Antoine, Alesia
AU - Alganem, Khaled
AU - Halpern, Madeline
AU - Deikus, Gintaras
AU - Shah, Hardik
AU - Fitzgerald, Megan
AU - Ladran, Ian
AU - Gochman, Peter
AU - Rapoport, Judith
AU - Tsankova, Nadejda M.
AU - McCullumsmith, Robert
AU - Hoffman, Gabriel E.
AU - Sebra, Robert
AU - Fang, Gang
AU - Brennand, Kristen J.
N1 - Funding Information:
K.J.B. is a New York Stem Cell Foundation—Robertson Investigator. This work was partially supported by National Institutes of Health (NIH) grants R01 MH121074 (K.J.B. and G.F.), R01 MH101454 (K.J.B.), R01 MH106056 (K.J.B.), R01 MH107487 (R.M.) and F31 MH112285 (E.F.), a Brain and Behavior Research Foundation Independent Investigator Grant (K.J.B.), a Brain Research Foundation Seed Grant (K.J.B.) and the New York Stem Cell Foundation (K.J.B.). We thank the Neuroscience and Stem Cell cores at Icahn School of Medicine at Mount Sinai. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. J. Simon drew the original illustrations used in the schematics shown in Figs. 3a and 6a,d,e. We acknowledge the Mount Sinai Neuropathology Research Core and Brain bank (J. Crary) for providing the human post-mortem brain tissue.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075779019&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075779019&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0539-z
DO - 10.1038/s41588-019-0539-z
M3 - Article
C2 - 31784728
AN - SCOPUS:85075779019
SN - 1061-4036
VL - 51
SP - 1679
EP - 1690
JO - Nature genetics
JF - Nature genetics
IS - 12
ER -