Brain and behavioural anomalies caused by<i>Tbx1</i>haploinsufficiency are corrected by vitamin B12
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 that <i>Tbx1</i> haploinsufficiency causes brain metabolic imbalance. We studied two mouse models of 22q11.2DS using mass spectrometry, nuclear magnetic resonance spectroscopy, and transcriptomics. We found that <i>Tbx1</i> <sup><i>+/-</i></sup> mice and <i>Df1/<sup>+</sup></i> mice, with a multigenic deletion that includes <i>Tbx1</i>, have elevated brain methylmalonic acid, which is highly brain-toxic. Focusing on <i>Tbx1</i> mutants, 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 in <i>Tbx1</i> <sup><i>+/-</i></sup> mice. Further studies will be required to establish whether the specific metabolites affected by <i>Tbx1</i> haploinsufficiency are potential biomarkers of brain disease status in 22q11.2DS patients.
Authors
- Claudia Angelini (ORCID: https://orcid.org/0000-0001-8350-8464)
- Annabella Tramice (ORCID: https://orcid.org/0000-0002-2425-2670)
- Marianna Caterino (ORCID: https://orcid.org/0000-0001-6035-8213)
- Gabriella Lania (ORCID: https://orcid.org/0000-0003-3681-0251)
- Silvia Mandillo (ORCID: https://orcid.org/0000-0002-4869-0974)
- Elvira De Leonibus (ORCID: https://orcid.org/0000-0003-0220-2864)
- Gemma Flore (ORCID: https://orcid.org/0000-0002-6058-2263)
- Michele Costanzo (ORCID: https://orcid.org/0000-0002-6386-2009)
- Elizabeth Illingworth (ORCID: https://orcid.org/0000-0002-9079-9121)
- Elisabetta Golini
- Diletta Cavezza (ORCID: https://orcid.org/0000-0003-0696-6968)
- Debora Paris (ORCID: https://orcid.org/0000-0003-4526-8353)
- Antonio Baldini (ORCID: https://orcid.org/0000-0002-5330-0256)
- Margherita Ruoppolo (ORCID: https://orcid.org/0000-0002-7364-0602)
- Andréa Motta (ORCID: https://orcid.org/0000-0002-8643-658X)
- Giulia Torromino (ORCID: https://orcid.org/0000-0002-7041-0289)
Institutions
- University of Salerno (IT)
- National Academies of Sciences, Engineering, and Medicine (US)
- Istituto per le Applicazioni del Calcolo Mauro Picone (IT)
- Center for Excellence in Molecular Cell Science (CN)
- National Research Council (RO)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- Assing (Italy) (IT)
- Institute of Genetics and Biophysics (IT)
- Telethon Institute Of Genetics And Medicine (IT)
- Institute of Cell Biology and Neurobiology (IT)
- University of Naples Federico II (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2024-11-20
- DOI
- https://doi.org/10.26508/lsa.202403075
- Citations
- 2
- Primary Topic
- Congenital heart defects research
- Type
- article
- Field-Weighted Citation Impact
- 0.47
Funders
- Ministero dell'Università e della Ricerca