LEMD3 is an inner nuclear membrane protein that functions as a negative regulator of TGF-beta, activin, and BMP signaling pathways through R-SMAD protein interactions 1. Beyond its classical role in suppressing these developmental signaling pathways, LEMD3 organizes three-dimensional chr12 architecture by anchoring heterochromatin at the nuclear periphery through interactions with CBX3, a reader of repressive histone marks 1. This chr12 organization function maintains vascular smooth muscle cell contractile identity; LEMD3 deficiency causes loss of the contractile phenotype and exacerbates intimal hyperplasia 1. In liver fibrosis, LEMD3 acts as a target of miR-223-3p to suppress hepatic stellate cell activation 2. Clinically, heterozygous LEMD3 loss-of-function mutations cause osteopoikilosis, a benign autosomal dominant disorder characterized by hyperostotic skeletal lesions 34. When osteopoikilosis associates with connective tissue skin nevi, it is termed Buschke-Ollendorff syndrome 45. LEMD3 mutations are responsible for Buschke-Ollendorff syndrome and osteopoikilosis but not isolated sporadic melorheostosis 56. The phenotype-genotype correlation in LEMD3-associated diseases shows substantial interfamilial and intrafamilial variability despite similar mutations 5.