2ys0

Structural highlights

Disease

[ENPP1_HUMAN] Defects in ENPP1 are a cause of increased susceptibility for ossification of the posterior longitudinal ligament of the spine (OPLL) [MIM:602475]. OPLL is a common form of human myelopathy with a prevalence of as much as 4% in a variety of ethnic groups.^[1] Defects in ENPP1 are the cause of arterial calcification of infancy, generalized, type 1 (GACI1) [MIM:208000]. A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure.^{[2] [3] [4] [5]} Defects in ENPP1 are associated with obesity, glucose intolerance, and type II diabetes non-insulin dependent (NIDDM) [MIM:125853].^[6] Defects in ENPP1 are the cause of rickets hypophosphatemic autosomal recessive type 2 (ARHR2) [MIM:613312]. ARHR2 is a hereditary form of hypophosphatemic rickets, a disorder of proximal renal tubule function that causes phosphate loss, hypophosphatemia and skeletal deformities, including rickets and osteomalacia unresponsive to vitamin D. Symptoms are bone pain, fractures and growth abnormalities.^{[7] [8]}

Function

[ENPP1_HUMAN] Involved primarily in ATP hydrolysis at the plasma membrane. Plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. In vitro, has a broad specificity, hydrolyzing other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling. Appears to modulate insulin sensitivity.^[9]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Nakamura I, Ikegawa S, Okawa A, Okuda S, Koshizuka Y, Kawaguchi H, Nakamura K, Koyama T, Goto S, Toguchida J, Matsushita M, Ochi T, Takaoka K, Nakamura Y. Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL). Hum Genet. 1999 Jun;104(6):492-7. PMID:10453738
2. ↑ Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, Schauer G, Lehmann M, Roscioli T, Schnabel D, Epplen JT, Knisely A, Superti-Furga A, McGill J, Filippone M, Sinaiko AR, Vallance H, Hinrichs B, Smith W, Ferre M, Terkeltaub R, Nurnberg P. Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification. Nat Genet. 2003 Aug;34(4):379-81. PMID:12881724 doi:10.1038/ng1221
3. ↑ Cheng KS, Chen MR, Ruf N, Lin SP, Rutsch F. Generalized arterial calcification of infancy: different clinical courses in two affected siblings. Am J Med Genet A. 2005 Jul 15;136(2):210-3. PMID:15940697 doi:10.1002/ajmg.a.30800
4. ↑ 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. PMID:15605415 doi:10.1002/humu.9297
5. ↑ 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. PMID:22209248 doi:10.1016/j.ajhg.2011.11.020
6. ↑ Bacci S, Ludovico O, Prudente S, Zhang YY, Di Paola R, Mangiacotti D, Rauseo A, Nolan D, Duffy J, Fini G, Salvemini L, Amico C, Vigna C, Pellegrini F, Menzaghi C, Doria A, Trischitta V. The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction. Diabetes. 2005 Oct;54(10):3021-5. PMID:16186408
7. ↑ 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. PMID:20137773 doi:10.1016/j.ajhg.2010.01.006
8. ↑ Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, Manor E, Buriakovsky S, Hadad Y, Goding J, Parvari R. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010 Feb 12;86(2):273-8. doi: 10.1016/j.ajhg.2010.01.010. Epub, 2010 Feb 4. PMID:20137772 doi:10.1016/j.ajhg.2010.01.010
9. ↑ Maddux BA, Goldfine ID. Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit. Diabetes. 2000 Jan;49(1):13-9. PMID:10615944