EBF2 variant identified in a patient with atypical partial lipodystrophy causes adipose fibrosis and dysfunction
Year: 2026
Type: article
Abstract: Lipodystrophy (LD) syndromes are characterized by loss of adipose tissue (AT), leading to insulin resistance and the development of metabolic syndrome. We identified a heterozygous nonsense variant in early B cell factor 2 (EBF2) (Chr8:26033143C>A, NM_022659.4: c.493G>T, p.E165X) in a patient with atypical partial LD (PLD). The EBF family is crucial for the differentiation and function of various mesenchymal tissues. Through in vitro and in vivo disease models, we discovered that this variant limited adipocyte differentiation and hampered AT remodeling. Heterozygous-knockin (Ebf2E165X/+) mice showed restricted adipogenesis and defective extracellular matrix remodeling during the post-weaning period and high-fat diet-induced (HFD-induced) AT expansion. A HFD caused abnormal adipocyte hypertrophy, decreased the expression of adiponectin and leptin, and led to glucose intolerance in Ebf2E165X/+ mice. Furthermore, key mitochondrial genes involved in fatty acid metabolism and oxidation were downregulated specifically in Ebf2E165X/+ AT. Our results suggest that EBF2 dysfunction caused by this nonsense variant drives disease pathology, establishing a connection between EBF2 disruption and an atypical form of LD.
DOI: 10.1172/jci192737
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G1565454821, G2795716607, G323183475, G3974007657, G7004715899, Clinical Implications of Genetically Defined Diabetes Subtypes and Application to Electronic Health Medical Record Systems, G9000013477, G9000091184, G9000124804, G9000214335, Michigan Diabetes Research Center (MDRC), Defining the molecular basis of thrombospondin-1-induced fibro-fatty diaphragm remodeling--a driver of obesity-associated respiratory dysfunction
OpenAlex ID: W7126169290