MOSMO (modulator of smoothened) is a membrane tetraspan protein that functions as a negative regulator of Hedgehog signaling 1. It acts as a component of the MMM (MEGF8-MOSMO-MGRN1) complex, a membrane-spanning E3 ubiquitin ligase that promotes internalization and subsequent degradation of the Smoothened (SMO) transducer protein located on the ciliary membrane 2. This mechanism attenuates Hedgehog pathway signaling strength and is essential for proper developmental patterning. MOSMO localizes to the plasma membrane, cytoplasmic vesicles, and primary cilium 1. MOSMO deficiency results in elevated SMO levels and increased Hedgehog signaling, causing multiple birth defects 3. Loss of both mosmo paralogs in zebrafish causes frontonasal hypoplasia and craniofacial skeleton defects 1. The gene is implicated in left-right body axis patterning and multi-organ development 2. Mutations in MOSMO are associated with the 16p12.1 chr16 deletion syndrome and may explain uncharacterized congenital craniofacial malformations 1. Additionally, MOSMO interacts synergistically with other neurodevelopmental genes like SETD5 to modulate neurodevelopmental phenotypes, suggesting a role in genetic interactions influencing birth defect penetrance 4.