Document Type
Article
Publication Date
9-29-2025
Original Citation
DiSanza B,
Porcari G,
Sertori Finoti L,
Ramos-Rodriguez L,
Burris D,
McDonough J,
Ning G,
Fagan G,
Helman G,
Weiss E,
Taft R,
Pizzino A,
Whitehead M,
Waldman A,
Simons C,
Ortiz-Gonzalez X,
Skarnes W,
Vanderver A,
Bhoj E,
Ahrens-Nicklas R.
Bi-allelic variants in BCAT1 impair mitochondrial function and are associated with a candidate neurometabolic disorder. HGG Adv. 2025;7(1):100525.
Keywords
JGM
JAX Source
HGG Adv. 2025;7(1):100525.
ISSN
2666-2477
PMID
41029903
DOI
https://doi.org/10.1016/j.xhgg.2025.100525
Abstract
Branched-chain amino acid transaminase-1 (BCAT1) initiates the catabolism of branched-chain amino acids (BCAAs), which are essential for neurologic function. However, the role of BCAT1 in neurodevelopment is largely unknown. Here, we identify compound heterozygous BCAT1 variants in a patient with a severe progressive neurodevelopmental syndrome. To investigate the functional consequences, we established patient variant (BCAT1: c.792T>A p.Phe264Leu; c.1042G>A p.Glu348Lys) and BCAT1 knockout hiPSC models. Both disease models show profound defects in cortical neuron differentiation and neurite outgrowth. Furthermore, metabolic analysis revealed evidence of mitochondrial dysfunction associated with increased levels of tricarboxylic acid (TCA) cycle intermediates, glutamate, and glutamine. This increase is linked to altered oxygen consumption rates, superoxide production, and upregulation of UCP2 in BCAT1 disease neurons, suggesting a downstream impact on electron transport chain homeostasis. These findings establish a regulatory role for BCAT1 in mitochondrial function and further define a role for genomic variants in BCAT1 in neurometabolic disorders.
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