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.

Department of Genetics University of Southern California Los Angeles USA

Department of Psychiatry Juntendo University Tokyo Japan

Department of Psychiatry University of California San Diego San Diego USA

Institute for Genomic Medicine University of California San Diego San Diego USA

Laboratory for Molecular Dynamics of Mental Disorders RIKEN Center for Brain Science Saitama Japan

Neurogenomics Division Translational Genomics Research Institute Arizona USA

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague Czechia

Section on Nephrology Department of Internal Medicine Wake Forest School of Medicine Winston Salem NC 27157 USA

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