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ENPP1 gene
URL of this page: https://medlineplus.gov/genetics/gene/enpp1/

ENPP1 gene

ectonucleotide pyrophosphatase/phosphodiesterase 1

Normal Function

The ENPP1 gene provides instructions for making a protein that helps break down a molecule called adenosine triphosphate (ATP). Specifically, the ENPP1 protein breaks down ATP that is found outside of cells (extracellular).  Extracellular ATP is quickly broken down into other molecules called adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate is important for preventing the accumulation of abnormal deposits of calcium (calcification) and other minerals (mineralization) in the body.

The ENPP1 protein also plays a role in the cell signaling that occurs in response to the hormone insulin. Part of the ENPP1 protein, called the SMB2 domain, interacts with the insulin receptor, which is a protein that binds to insulin and initiates cell signaling. Insulin plays many roles in the body. It helps regulate levels of blood glucose (also called blood sugar) by controlling how much glucose passes from the bloodstream into cells to be used as energy. Insulin is also important for the maintenance of the outer layer of skin (the epidermis). It helps control the transport of the pigment melanin from the cells that produce it (melanocytes) to epidermal cells called keratinocytes. Insulin is also involved in the development of keratinocytes.

Health Conditions Related to Genetic Changes

Cole disease

Variants (also called mutations) in the ENPP1 gene have been identified in people with Cole disease. People with this condition typically have areas of unusually light-colored skin (hypopigmentation) on the arms and legs and spots of thickened skin on the palms of the hands and the soles of the feet (punctate palmoplantar keratoderma).

The ENPP1 gene variants that cause Cole disease lead to a change in the structure of the SMB2 domain, which alters its interaction with the insulin receptor and affects cell signaling. These variants cause cells to make a version of the ENPP1 protein that does not function properly. As a result, ENPP1's role in melanin transport and keratinocyte development are impaired, which leads to hypopigmentation and the punctate palmoplantar keratoderma. The protein's role in calcification may also be impaired, which likely accounts for the abnormal calcium deposits that occur in some affected individuals. For reasons that are unclear, the changes in insulin signaling that are caused by these ENPP1 gene variants do not seem to affect blood glucose control.

More About This Health Condition

Generalized arterial calcification of infancy

Variants in the ENPP1 gene have been identified in individuals with generalized arterial calcification of infancy (GACI), a life-threatening disorder that is characterized by calcification in the blood vessels that carry blood from the heart to the rest of the body (the arteries). People with variants in the ENPP1 gene may produce an altered version of the ENPP1 protein that cannot properly assist in the breakdown of ATP and the production of pyrophosphate. Reduced availability of pyrophosphate likely interferes with the regulation of calcification in the body, leading to the signs and symptoms seen in infants with GACI.

More About This Health Condition

Other disorders

Variants in the ENPP1 gene are a rare cause of hypophosphatemic rickets. This condition is characterized by low levels of phosphate in the blood (hypophosphatemia), which can lead to skeletal abnormalities. Phosphate is a mineral that is essential for the normal development of bones and teeth. A lack of phosphate can cause weakening or softening of the bones (rickets). Through a poorly understood mechanism, the variants in the ENPP1 gene that cause hypophosphatemic rickets increase the amount of a protein called fibroblast growth factor 23. This protein works within the kidneys to maintain the proper amount of phosphate in the body. When ENPP1 gene variants cause an increase in the amount of fibroblast growth factor 23, less phosphate is available for normal bone development and maintenance, which contributes to the skeletal abnormalities seen in people with hypophosphatemic rickets.

A normal variation (polymorphism) in the ENPP1 gene has been associated with an increased risk of type 2 diabetes (the most common form of diabetes). Type 2 diabetes is caused by resistance to insulin, which results in impaired control of blood glucose. People with this polymorphism have a version of the ENPP1 protein where the protein building block (amino acid) glutamine replaces the amino acid lysine at protein position 121. This altered version of the protein is called Q121, while the version of the protein with lysine is known as K121. The Q121 variant of the ENPP1 protein inhibits the function of the insulin receptor more than the K121 version. This increases insulin resistance and the risk of type 2 diabetes.

Other Names for This Gene

  • PC-1
  • PCA1

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Bacci S, De Cosmo S, Prudente S, Trischitta V. ENPP1 gene, insulin resistance and related clinical outcomes. Curr Opin Clin Nutr Metab Care. 2007 Jul;10(4):403-9. doi: 10.1097/MCO.0b013e3281e386c9. Citation on PubMed
  • Collins L, Sandy J, Ly S, Lomax KE, Black S, McKenzie F, Hayes E, Poulton C, Jefferies C, Hunter W, Simm P, Rodda C, Biggin A, Munns C, Siafarikas A. Six cases of ENPP1 pathogenic variants causing autosomal recessive hypophosphatemic rickets type 2 and generalized arterial calcification of infancy. JBMR Plus. 2025 Dec 6;9(Suppl 5):v47-v57. doi: 10.1093/jbmrpl/ziae174. eCollection 2025 Dec. Citation on PubMed
  • Edouard T, Linglart A. Autosomal recessive hypophosphatemic rickets type 2 due to ENPP1 deficiency (ARHR2). Arch Pediatr. 2024 Sep;31(4S1):4S27-4S32. doi: 10.1016/S0929-693X(24)00154-4. Citation on PubMed
  • Eytan O, Morice-Picard F, Sarig O, Ezzedine K, Isakov O, Li Q, Ishida-Yamamoto A, Shomron N, Goldsmith T, Fuchs-Telem D, Adir N, Uitto J, Orlow SJ, Taieb A, Sprecher E. Cole Disease Results from Mutations in ENPP1. Am J Hum Genet. 2013 Oct 3;93(4):752-7. doi: 10.1016/j.ajhg.2013.08.007. Epub 2013 Sep 26. Citation on PubMed or Free article on PubMed Central
  • Galletti S, Nitschke Y, Malavolti AM, Aquilano G, Faldella G, Corvaglia L, Rutsch F. Generalized Arterial Calcification of Infancy: Fatal Clinical Course Associated with a Novel Mutation in ENPP1. JIMD Rep. 2011;1:23-7. doi: 10.1007/8904_2011_11. Epub 2011 Jun 25. Citation on PubMed or Free article on PubMed Central
  • Kalal IG, Seetha D, Panda A, Nitschke Y, Rutsch F. Molecular diagnosis of generalized arterial calcification of infancy (GACI). J Cardiovasc Dis Res. 2012 Apr;3(2):150-4. doi: 10.4103/0975-3583.95373. Citation on PubMed or Free article on PubMed Central
  • Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010 Feb 12;86(2):267-72. doi: 10.1016/j.ajhg.2010.01.006. Epub 2010 Feb 4. Citation on PubMed or Free article on PubMed Central
  • Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J, Le Merrer M, Guest G, Lambot K, Tazarourte-Pinturier MF, Chassaing N, Roche O, Feenstra I, Loechner K, Deshpande C, Garber SJ, Chikarmane R, Steinmann B, Shahinyan T, Martorell L, Davies J, Smith WE, Kahler SG, McCulloch M, Wraige E, Loidi L, Hohne W, Martin L, Hadj-Rabia S, Terkeltaub R, Rutsch F. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012 Jan 13;90(1):25-39. doi: 10.1016/j.ajhg.2011.11.020. Epub 2011 Dec 29. Citation on PubMed or Free article on PubMed Central
  • Ralph D, Levine MA, Richard G, Morrow MM, Flynn EK, Uitto J, Li Q. Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma. Hum Mutat. 2022 Sep;43(9):1183-1200. doi: 10.1002/humu.24391. Epub 2022 May 18. Citation on PubMed
  • Ruf N, Uhlenberg B, Terkeltaub R, Nurnberg P, Rutsch F. The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI). Hum Mutat. 2005 Jan;25(1):98. doi: 10.1002/humu.9297. Citation on PubMed

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