Brain and behavioural anomalies caused byhaploinsufficiency are corrected by vitamin B12.

Abstract

The brain-related phenotypes observed in 22q11.2 deletion syndrome (DS) patients are highly variable, and their origin is poorly understood. Changes in brain metabolism might contribute to these phenotypes, as many of the deleted genes are involved in metabolic processes, but this is unknown. This study shows for the first time thathaploinsufficiency causes brain metabolic imbalance. We studied two mouse models of 22q11.2DS using mass spectrometry, nuclear magnetic resonance spectroscopy, and transcriptomics. We found thatmice andmice, with a multigenic deletion that includes, have elevated brain methylmalonic acid, which is highly brain-toxic. Focusing onmutants, we found that they also have a more general brain metabolomic imbalance that affects key metabolic pathways, such as glutamine-glutamate and fatty acid metabolism. We provide transcriptomic evidence of a genotype-vitamin B12 treatment interaction. In addition, vitamin B12 treatment rescued a behavioural anomaly inmice. Further studies will be required to establish whether the specific metabolites affected byhaploinsufficiency are potential biomarkers of brain disease status in 22q11.2DS patients.