학술논문
Precise Therapeutic Targeting of Distinct NRXN1 +/- Mutations.
Document Type
Author
Fernando MB; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Friedman Brain Institute, Black Family Stem Cell Institute, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06520.; Fan Y; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Zhang Y; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Kammourh S; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Murphy AN; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Friedman Brain Institute, Black Family Stem Cell Institute, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Ghorbani S; Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06520.; Haukeland University Hospital, Bergen, Norway.; Onatzevitch R; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Pero A; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Padilla C; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Flaherty EK; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Prytkova IK; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Cao L; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Williams S; Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Friedman Brain Institute, Black Family Stem Cell Institute, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Fang G; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Slesinger PA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Brennand KJ; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Friedman Brain Institute, Black Family Stem Cell Institute, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.; Department of Psychiatry, Yale School of Medicine, New Haven, CT, 06520.
Source
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
As genetic studies continue to identify risk loci that are significantly associated with risk for neuropsychiatric disease, a critical unanswered question is the extent to which diverse mutations--sometimes impacting the same gene-- will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1 , a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique (non-recurrent) deletions. We contrast the cell-type-specific impact of patient-specific mutations in NRXN1 using human induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Via distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1 + / - deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Stratification of patients by LOF and GOF mechanisms will facilitate individualized restoration of NRXN1 isoform repertoires; towards this, antisense oligonucleotides knockdown mutant isoform expression and alters synaptic transcriptional signatures, while treatment with β-estradiol rescues synaptic function in glutamatergic neurons. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disease, our findings add nuance to future considerations of precision medicine.