PORCN

PORCN, or porcupine homolog O-acyltransferase, is a human gene encoding an endoplasmic reticulum–resident membrane protein essential for Wnt signaling. It is a member of the membrane-bound O-acyltransferase (MBOAT) family. The enzyme palmitoleoylates Wnt proteins, a lipid modification required for their proper folding, secretion, and activity. Palmitoylated Wnts are packaged into secretory vesicles and exported to signal to Frizzled receptors and LRP5/6 co-receptors on adjacent cells. Without PORCN activity, Wnt proteins are largely retained in the endoplasmic reticulum and signaling is markedly reduced, affecting both canonical and non-canonical Wnt pathways. Expression of PORCN is broad, consistent with the widespread role of Wnt signaling in development and tissue homeostasis.

Genetics and disease: PORCN is located on the X chromosome (Xp11.23). Pathogenic variants cause Goltz syndrome (focal dermal hypoplasia), a rare X-linked dominant developmental disorder characterized by skin defects, skeletal anomalies, and facial abnormalities. Phenotypes are often mosaic due to X-chromosome inactivation. Functional disruption of PORCN in model organisms leads to severe loss of Wnt signaling and embryonic lethality in mice, underscoring its essential role in development.

Clinical research and therapeutics: Because PORCN is required for Wnt ligand secretion, PORCN inhibitors have been developed to dampen aberrant Wnt signaling in cancers and fibrotic diseases. Examples include LGK974 (WNT974), ETC-159, and other inhibitors in clinical trials, though their use is balanced by potential effects on normal tissue homeostasis.

Origin of name: The gene was named as a homolog of the Drosophila porcupine gene, discovered for its role in wing development; the protein family is called PORCN/MBOAT, reflecting the porcupine phenotype in flies.