Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca2+ pump

Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characte rized by suprabasal cell separation (acantholysis) of the epidermis. Previo us genetic linkage studies localized the gene to a 5 cM interval on human c hromosome 3q21, After reducing the disease critical region to tl cM, we use d a positional cloning strategy to identify the gene ATP2C1, which is mutat ed in HHD, ATP2C1 encodes a new class of P-type Ca2+-transport ATPase, whic h is the homologue for the rat SPLA and the yeast PMR1 medial Golgi Ca2+ pu mps and is related to the sarco(endo)plasmic calcium ATPase (SERCA) and pla sma membrane calcium ATPase (PCMA) families of Ca2+ pumps. The predicted pr otein has the same apparent transmembrane organization and contains all of the conserved domains present in other P-type ATPases, ATP2C1 produces two alternative splice variants of similar to 4.5 kb encoding predicted protein s of 903 and 923 amino acids. We identified 13 different mutations, includi ng nonsense, frameshift insertion and deletions, splice-site mutations, and nonconservative missense mutations. This study demonstrates that defects i n ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the cr itical role of Ca2+ signaling in maintaining epidermal integrity.