Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

Marianna Caterino, Debora Paris, Giulia Torromino, Michele Costanzo, Gemma Flore, Annabella Tramice, Elisabetta Golini, Silvia Mandillo, Diletta Cavezza, Claudia Angelini, Margherita Ruoppolo, Andrea Motta, Elvira De Leonibus, Antonio Baldini, Elizabeth Illingworth, Gabriella Lania
2024 · doi:10.1101/2024.02.01.578212
preprint OA: closed
📄 Open PDF View at publisher

Abstract

Introduction The brain-related phenotypes observed in 22q11.2 deletion syndrome (22q11.2DS) are highly variable and their origin is poorly understood. Changes in brain metabolism may cause or contribute to the phenotypes, given that many of the deleted genes (approx. 10%) are implicated in metabolic processes, but this is currently unknown. It is clearly important to address this knowledge gap, but in humans, the primary material required for studying brain metabolism is inaccessible. For this reason, we sought to address the issue using two mouse models of 22q11.2DS. Methods We used three independent approaches to investigate brain metabolism in young adult mice, namely, mass spectrometry, nuclear magnetic resonance spectroscopy and transcriptomics. We selected to study primarily Tbx1 single gene mutants because it is the primary candidate disease gene. We then confirmed key findings in the multi-gene deletion mutant Df1/+ . Results We found that Tbx1 mutants have alterations of specific brain metabolites, including methylmalonic acid, which is highly brain-toxic, as well as a more general metabolomic imbalance. We provide transcriptomic evidence of an interaction genotype-vB12 treatment, and behavioural evidence of a response to vB12 treatment, which rescued some of the behavioural anomaly observed in Tbx1 mutants. We conclude that Tbx1 haploinsufficiency causes extensive brain metabolic anomalies, which are partially responsive to vB12 treatment. We suggest that alterations of glutamine-glutamate metabolism and fatty acid metabolism are key components of the metabolic phenotype in these mutants.

My notes (saved in your browser only)

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2024) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.

References (51)

Source provenance

crossref
last seen: 2026-07-10T06:41:21.364107+00:00
europepmc
last seen: 2026-05-20T01:45:00.602351+00:00
unpaywall
last seen: 2026-07-18T06:52:13.688204+00:00