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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

K. Nakajima, A. Miranda, DW. Craig, T. Shekhtman, S. Kmoch, A. Bleyer, S. Szelinger, T. Kato, JR. Kelsoe

. 2020 ; 10 (1) : 407. [pub] 20201124

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21019800

Grant support
18H05435 MEXT | Japan Society for the Promotion of Science (JSPS) - International
19km0405208h000 Japan Agency for Medical Research and Development (AMED) - International
MH094483 U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) - International
R01 MH094483 NIMH NIH HHS - United States
T32 GM008666 NIGMS NIH HHS - United States
19dm0207074h0001 Japan Agency for Medical Research and Development (AMED) - International
17H01573 MEXT | Japan Society for the Promotion of Science (JSPS) - International
NV17-29786A MZ0 CEP Register

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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