Biallelic TXNIP deficiency is associated with a multisystemic metabolic disease

Thioredoxin-interacting protein (TXNIP) is a protein involved in redox metabolism, but also a key regulator of glucose and lipid metabolism in preclinical models. To date, four patients with biallelic loss-of-function variants in TXNIP have been described, presenting with lactic acidosis and variable hypoglycemia, hepatomegaly, developmental delay and seizures. However, the role of TXNIP in human metabolism and its mechanistic effects across different organs are not fully understood.

We clinically, biochemically and genetically characterized a cohort of six additional individuals with biallelic pathogenic variants in TXNIP. Organ specimens from patients and mice were analyzed by gene expression, histology, and lipidomic and proteomic profiling.

We confirmed lactic acidosis as the main clinical sign and added adult-onset cardiomyopathy, skeletal muscle weakness, and dyslipidemia to the extended disease spectrum. Heart, liver and muscle patient specimens showed pathological lipid accumulation, and mechanistic studies uncovered increased fatty acid synthesis markers and complex rearrangements of the lipidome and proteome. In Txnip-deficient mice, restricting dietary carbohydrates partially rescued fatty acid synthesis markers and lipid storage in the heart but led to dyslipidemia.

Our studies show that TXNIP is an important metabolic modifier in cardiac and skeletal muscle as well as in lipoprotein metabolism and that biallelic pathogenic variants in TXNIP lead to a pleiotropic disease affecting cellular lipid metabolism in multiple organ systems, with potentially fatal adult-onset cardiomyopathy.