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 - 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.
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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 -