Abstract |
Brain-derived neurotrophic factor ( BDNF) signals through its high affinity receptor Tropomyosin receptor kinase-B (TrkB) to regulate neuronal development, synapse formation and plasticity. In rodents, genetic disruption of Bdnf and TrkB leads to weight gain and a spectrum of neurobehavioural phenotypes. Here, we functionally characterised a de novo missense variant in BDNF and seven rare variants in TrkB identified in a large cohort of people with severe, childhood-onset obesity. In cells, the E183K BDNF variant resulted in impaired processing and secretion of the mature peptide. Multiple variants in the kinase domain and one variant in the extracellular domain of TrkB led to a loss of function through multiple signalling pathways, impaired neurite outgrowth and dominantly inhibited glutamatergic synaptogenesis in hippocampal neurons. BDNF/TrkB variant carriers exhibited learning difficulties, impaired memory, hyperactivity, stereotyped and sometimes, maladaptive behaviours. In conclusion, human loss of function BDNF/TrkB variants that impair hippocampal synaptogenesis may contribute to a spectrum of neurobehavioural disorders.
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Authors | Takuhiro Sonoyama, Lukas K J Stadler, Mingyan Zhu, Julia M Keogh, Elana Henning, Fuki Hisama, Peter Kirwan, Magdalena Jura, Beata K Blaszczyk, David C DeWitt, Bas Brouwers, Marko Hyvönen, Inês Barroso, Florian T Merkle, Suzanne M Appleyard, Gary A Wayman, I Sadaf Farooqi |
Journal | Scientific reports
(Sci Rep)
Vol. 10
Issue 1
Pg. 9028
(06 03 2020)
ISSN: 2045-2322 [Electronic] England |
PMID | 32493978
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Brain-Derived Neurotrophic Factor
- BDNF protein, human
- Protein Kinases
- Receptor, trkB
- tropomyosin kinase
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Topics |
- Adolescent
- Brain-Derived Neurotrophic Factor
(metabolism)
- Child
- Child, Preschool
- Female
- Hippocampus
(metabolism, physiology)
- Humans
- Male
- Neurogenesis
(drug effects, physiology)
- Neuronal Outgrowth
(drug effects)
- Neurons
(metabolism)
- Phosphorylation
- Protein Kinases
- Receptor, trkB
(metabolism)
- Signal Transduction
(drug effects)
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