Preprint links truncating ASXL1 variants to Warburg-like metabolic rewiring via mitochondrial pyruvate carrier repression

A preprint posted to bioRxiv reports that truncating variants in ASXL1, the gene mutated in Bohring-Opitz syndrome (BOS; OMIM #605309), drive a Warburg-like metabolic state in patient-derived dermal fibroblasts. ASXL1 encodes a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB deubiquitinase complex with BAP1. Truncating ASXL1 variants are also recurrent somatic driver mutations in myeloid leukaemias, making this an unusual gene where identical molecular lesions occur in both a rare constitutional neurodevelopmental syndrome and in somatic cancer.

Using fibroblasts derived from individuals with BOS, the authors show that ASXL1 truncation increases glycolytic flux and causes accumulation of pyruvate, consistent with repression of the mitochondrial pyruvate carrier (MPC) — the complex that shuttles pyruvate from the cytoplasm into mitochondria for oxidative metabolism. The Warburg effect, originally described in tumour cells, refers to preferential reliance on glycolysis even in the presence of oxygen; its appearance in a constitutional syndrome model is an unusual finding.

The work raises questions about whether metabolic dysregulation contributes to the neurodevelopmental features of BOS, and whether shared metabolic mechanisms link germline and somatic ASXL1 pathology. It also highlights patient-derived fibroblasts as a tractable model for investigating epigenetic regulator function. This work is a preprint and has not yet completed peer review.