Ntrk1  mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice

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Abstract

Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.

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Author and article information

Contributors

Tadafumi Kato:

ORCID: http://orcid.org/0000-0001-7856-3952

tadafumi.kato@juntendo.ac.jp

John R. Kelsoe:

ORCID: http://orcid.org/0000-0002-3013-2333

jkelsoe@ucsd.edu

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 24 November 2020

Publication date PMC-release: 24 November 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 407

Affiliations

[1 ]GRID grid.474690.8, Laboratory for Molecular Dynamics of Mental Disorders, , RIKEN Center for Brain Science, ; Saitama, Japan

[2 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Psychiatry, , University of California San Diego, ; San Diego, USA

[3 ]GRID grid.42505.36, ISNI 0000 0001 2156 6853, Department of Genetics, , University of Southern California, ; Los Angeles, USA

[4 ]GRID grid.4491.8, ISNI 0000 0004 1937 116X, Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, , Charles University, ; Prague, Czechia

[5 ]GRID grid.241167.7, ISNI 0000 0001 2185 3318, Section on Nephrology, Department of Internal Medicine, , Wake Forest School of Medicine, ; Winston-Salem, NC 27157 USA

[6 ]GRID grid.250942.8, ISNI 0000 0004 0507 3225, Neurogenomics Division, , Translational Genomics Research Institute, ; Arizona, USA

[7 ]GRID grid.258269.2, ISNI 0000 0004 1762 2738, Department of Psychiatry, , Juntendo University, ; Tokyo, Japan

[8 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Institute for Genomic Medicine, , University of California San Diego, ; San Diego, USA

Author information

Alannah Miranda http://orcid.org/0000-0002-8749-2073

Tadafumi Kato http://orcid.org/0000-0001-7856-3952

John R. Kelsoe http://orcid.org/0000-0002-3013-2333

Article

Publisher ID: 1087

DOI: 10.1038/s41398-020-01087-8

PMC ID: 7687911

PubMed ID: 33235206

SO-VID: c040d7cc-b188-4d5e-ba13-7f4d38bdf548

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 17 February 2020

Date revision received : 28 September 2020

Date accepted : 20 October 2020

Funding

Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);

Award ID: MH094483

Award Recipient : Alannah Miranda John R. Kelsoe

Funded by: FundRef https://doi.org/10.13039/100000057, U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS);

Award ID: T32 GM008666

Award Recipient : Alannah Miranda

Funded by: FundRef https://doi.org/10.13039/501100001691, MEXT | Japan Society for the Promotion of Science (JSPS);

Award ID: 18H05435

Award ID: 17H01573

Award ID: 18H05435

Award ID: 17H01573

Award Recipient : Kazuo Nakajima Tadafumi Kato

Funded by: FundRef https://doi.org/10.13039/100009619, Japan Agency for Medical Research and Development (AMED);

Award ID: 19km0405208h000

Award ID: 19dm0207074h0001

Award ID: 19km0405208h000

Award ID: 19dm0207074h0001

Award Recipient : Kazuo Nakajima Tadafumi Kato

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)

Custom metadata

ScienceOpen disciplines: Clinical Psychology & Psychiatry

Keywords: stem cells,molecular neuroscience,bipolar disorder

Data availability:

ScienceOpen disciplines: Clinical Psychology & Psychiatry

Keywords: stem cells, molecular neuroscience, bipolar disorder

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Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice

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