Identification of a novel genetic mechanism underlying partial lipodystrophy

Lipodystrophy syndromes are a heterogeneous group of disorders characterized by partial or near-total absence of subcutaneous adipose tissue, often associated with severe metabolic complications such as insulin resistance, dyslipidemia, and hepatic steatosis. These syndromes may result from either acquired or genetic causes, the latter involving pathogenic variants in genes crucial for adipocyte differentiation, lipid storage, or adipose tissue homeostasis. However, in a subset of patients, the molecular basis remains unknown, suggesting the existence of additional mechanisms underlying adipose tissue dysfunction. In this study, we identified a novel heterozygous nonsense variant in early B cell factor 2 (EBF2, 8:26033143C>A, c.493G>T, p.E165X) in a patient with atypical partial lipodystrophy featuring adipose fibrosis and metabolic complications. EBF2 is a transcription factor regulating brown and beige adipocyte differentiation, though its function in white adipose tissue remains poorly defined. To investigate whether this variant could be causative of the patient’s clinical phenotype, we performed complementary in vitro and in vivo studies. Cellular analyses demonstrated that the EBF2 p.E165X variant markedly impairs adipocyte differentiation, leading to reduced lipid accumulation and downregulation of key adipocyte markers. In vivo analyses of heterozygous knock-in (Ebf2E165X/+) mice revealed structural abnormalities in white adipose tissue, including increased extracellular matrix deposition and mitochondrial alterations, along with altered metabolic responses to high-fat diet feeding. Mechanistically, the truncated EBF2 (1-164) protein appears to exert a dominant-negative effect, interfering with the transcriptional activity of the wild-type protein and potentially impairing H3K27Ac-dependent activation of EBF2 target genes involved in adipocyte differentiation. Altogether, this work identifies EBF2 as a critical regulator of white adipose tissue differentiation and function. It provides new insights into adipose tissue biology and identifies a previously unrecognized genetic cause of partial lipodystrophy, expanding the current spectrum of genes implicated in these disorders.