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PMID: 31784728 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Neuronal impact of patient-specific aberrant NRXN1α splicing.

Nature genetics ·Vol. 51 ·No. 12 ·2019-00-00 ·Pages 1679-1690

Flaherty E, Zhu S, Barretto N, Cheng E, Deans PJM, Fernando MB, Schrode N, Francoeur N, Antoine A, Alganem K, Halpern M, Deikus G, Shah H, Fitzgerald M, Ladran I, Gochman P, Rapoport J, Tsankova NM, McCullumsmith R, Hoffman GE, Sebra R, Fang G, Brennand KJ

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 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.

MeSH Terms
Alternative Splicing Animals Autism Spectrum Disorder/genetics Bipolar Disorder/genetics Calcium-Binding Proteins/genetics Case-Control Studies Depressive Disorder, Major/genetics Female Gene Expression Heterozygote Humans Induced Pluripotent Stem Cells/physiology Male Mice Neural Cell Adhesion Molecules/genetics Protein Isoforms/genetics Schizophrenia/genetics Sequence Deletion
Chemicals
Calcium-Binding Proteins NRXN1 protein, human Neural Cell Adhesion Molecules Nrxn1 protein, mouse Protein Isoforms
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Flaherty Erin
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Zhu Shijia
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Barretto Natalie ORCID
Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Cheng Esther
Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Deans P J Michael
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Fernando Michael B ORCID
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Schrode Nadine ORCID
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Francoeur Nancy
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Antoine Alesia
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alganem Khaled
Department of Neurosciences, Institute in the College of Medicine & Life Sciences, The University of Toledo, Toledo, OH, USA.
Halpern Madeline
Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Deikus Gintaras
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Shah Hardik
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Fitzgerald Megan
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ladran Ian
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Gochman Peter
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Rapoport Judith
Childhood Psychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
Tsankova Nadejda M
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
McCullumsmith Robert
Department of Neurosciences, Institute in the College of Medicine & Life Sciences, The University of Toledo, Toledo, OH, USA.
Hoffman Gabriel E ORCID
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sebra Robert
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Fang Gang ORCID
Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
Brennand Kristen J ORCID
Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected]. | Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/s41588-019-0539-z
Email
[email protected]
[email protected]
Published
2019-00-00
Epub
2019-00-29
Pages
1679-1690
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC7451045
Subset
IM
Grants
NIMH NIH HHS · F31 MH112285 · United States
NIH HHS · S10 OD018522 · United States
NIMH NIH HHS · R21 MH107916 · United States
NIMH NIH HHS · R01 MH106056 · United States
NIMH NIH HHS · R01 MH107487 · United States
NIMH NIH HHS · R01 MH101454 · United States
NIMH NIH HHS · R01 MH121074 · United States
External Links
PubMed source DOI: 10.1038/s41588-019-0539-z PMC Full Text View journal details
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