Compound heterozygous PROC mutations cause lipedema in humans

Lipedema is a hereditary disorder characterized by excessive accumulation of subcutaneous adipose tissue in the limbs. The genetic causes and mechanisms underlying abnormal adipocyte expansion in lipedema, however, remain unknown. Here, we identify compound heterozygous mutations in the PROC gene in three lipedema patients from two unrelated consanguineous families. In vitro studies demonstrate the wild-type Protein C (PC), encoded by PROC, plays an inhibitory role in adipogenesis; conversely, the identified PC mutants, p.R271Q and p.R272H, fail to inhibit this process. In mice, the receptor of PC (PROCR) marks adipocyte progenitors, and conditional deletion of PROCR in these cells leads to an increased number of newborn adipocytes within white adipose tissue (WAT). Transcriptomic analysis alongside chemical blockage tests identifies HIF-1α as a primary downstream transcription factor mediating PC–PROCR signaling in adipogenesis. Furthermore, adipose biopsy samples from the patients’ thighs exhibit hyperplastic expansion of adipocytes, while single-nucleus RNA sequencing confirms increased adipogenic capacity and down-regulated HIF-1α activity in affected subjects. These findings establish PROC as the first causal gene for human lipedema and unveil a previously unexpected role of the PC–PROCR axis in orchestrating adipogenesis.