The ANKH gene provides instructions for making a protein that is involved in skeletal development. The ANKH protein plays a role in the development and function of cells that build bones (osteoblasts) and cells that break down bone (osteoclasts). Osteoclasts are involved in bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. In addition, the ANKH protein transports a molecule called pyrophosphate out of cells to the intricate network of proteins that forms in the spaces between cells (extracellular matrix). This extracellular pyrophosphate helps regulate bone formation by preventing mineralization, the process by which minerals such as calcium and phosphorus are deposited in tissues. The ANKH protein may have other, unknown functions.
Health Conditions Related to Genetic Changes
More than 10 mutations in the ANKH gene have been found to cause autosomal dominant craniometaphyseal dysplasia, a condition characterized by thickening of bones in the skull (cranium) and widening of a region at the end of long bones known as the metaphysis. Some mutations change a single protein building block (amino acid) in the ANKH protein, whereas others insert or delete one or more amino acids in the protein. These changes disrupt the functioning of osteoblasts and osteoclasts. In particular, the maturation (differentiation) of osteoclasts is impaired, which likely disrupts bone remodeling. Reduced breakdown of bone tissue can contribute to the bone thickening characteristic of craniometaphyseal dysplasia. The altered ANKH proteins may also be less able to transport pyrophosphate out of cells. A shortage of extracellular pyrophosphate can increase bone mineralization, which may also contribute to the bone abnormalities.More About This Health Condition
At least five mutations in the ANKH gene have been found to cause a rare hereditary form of a cartilage disorder called calcium pyrophosphate dihydrate deposition disease (CPPDD). CPPDD, also called chondrocalcinosis or pseudogout, is characterized by the accumulation of calcium pyrophosphate dihydrate crystals in the cartilage, the tough but flexible tissue that covers the ends of bones at the joints. The buildup of these crystals weakens cartilage and causes it to break down more easily. The crystals may cause inflammation in the joints, which can be painful.
Most cases of CPPDD occur in people older than 40, are not inherited, and have an unknown cause. However, inherited mutations in the ANKH gene have been shown to cause CPPDD in a few families. In these families, one altered copy of the ANKH gene in each cell is sufficient to cause the condition. Individuals with familial CPPDD caused by ANKH gene mutations typically form crystal deposits within multiple joints during early adulthood. Researchers believe that these mutations lead to elevated pyrophosphate levels in the extracellular matrix. High levels of pyrophosphate result in excessive formation of calcium pyrophosphate dihydrate crystals within joints.
Studies suggest that certain variations (polymorphisms) in the ANKH gene are associated with the normal differences in bone size and shape among individuals. These polymorphisms probably result in slight changes in the activity of the ANKH protein, affecting the levels of pyrophosphate in the extracellular matrix.
Other Names for This Gene
- ankylosis, progressive homolog (mouse)
- progressive ankylosis protein
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
- Addison WN, Azari F, Sorensen ES, Kaartinen MT, McKee MD. Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 2007 May 25;282(21):15872-83. doi: 10.1074/jbc.M701116200. Epub 2007 Mar 23. Citation on PubMed
- Chen IP, Luxmi R, Kanaujiya J, Hao Z, Reichenberger EJ. Craniometaphyseal Dysplasia Mutations in ANKH Negatively Affect Human Induced Pluripotent Stem Cell Differentiation into Osteoclasts. Stem Cell Reports. 2017 Nov 14;9(5):1369-1376. doi: 10.1016/j.stemcr.2017.09.016. Epub 2017 Oct 19. Citation on PubMed or Free article on PubMed Central
- Chen IP, Wang L, Jiang X, Aguila HL, Reichenberger EJ. A Phe377del mutation in ANK leads to impaired osteoblastogenesis and osteoclastogenesis in a mouse model for craniometaphyseal dysplasia (CMD). Hum Mol Genet. 2011 Mar 1;20(5):948-61. doi: 10.1093/hmg/ddq541. Epub 2010 Dec 13. Citation on PubMed or Free article on PubMed Central
- Gurley KA, Reimer RJ, Kingsley DM. Biochemical and genetic analysis of ANK in arthritis and bone disease. Am J Hum Genet. 2006 Dec;79(6):1017-29. doi: 10.1086/509881. Epub 2006 Oct 16. Citation on PubMed or Free article on PubMed Central
- Korostishevsky M, Vistoropsky Y, Malkin I, Kobyliansky E, Livshits G. Anthropometric and bone-related biochemical factors are associated with different haplotypes of ANKH locus. Ann Hum Biol. 2008 Sep-Oct;35(5):535-46. doi: 10.1080/03014460802304588. Citation on PubMed
- Malkin I, Dahm S, Suk A, Kobyliansky E, Toliat M, Ruf N, Livshits G, Nurnberg P. Association of ANKH gene polymorphisms with radiographic hand bone size and geometry in a Chuvasha population. Bone. 2005 Feb;36(2):365-73. doi: 10.1016/j.bone.2004.09.002. Citation on PubMed
- Malkin I, Ermakov S, Kobyliansky E, Livshits G. Strong association between polymorphisms in ANKH locus and skeletal size traits. Hum Genet. 2006 Aug;120(1):42-51. doi: 10.1007/s00439-006-0173-6. Epub 2006 Apr 26. Citation on PubMed
- Nurnberg P, Thiele H, Chandler D, Hohne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K, Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F, Mundlos S, Braun HS, Laing N, Tinschert S. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet. 2001 May;28(1):37-41. doi: 10.1038/ng0501-37. Citation on PubMed
- Pendleton A, Johnson MD, Hughes A, Gurley KA, Ho AM, Doherty M, Dixey J, Gillet P, Loeuille D, McGrath R, Reginato A, Shiang R, Wright G, Netter P, Williams C, Kingsley DM. Mutations in ANKH cause chondrocalcinosis. Am J Hum Genet. 2002 Oct;71(4):933-40. doi: 10.1086/343054. Epub 2002 Sep 20. Citation on PubMed or Free article on PubMed Central
- Reichenberger E, Chen IP. Craniometaphyseal Dysplasia, Autosomal Dominant. 2007 Aug 27 [updated 2020 Jun 11]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from http://www.ncbi.nlm.nih.gov/books/NBK1461/ Citation on PubMed
- Reichenberger E, Tiziani V, Watanabe S, Park L, Ueki Y, Santanna C, Baur ST, Shiang R, Grange DK, Beighton P, Gardner J, Hamersma H, Sellars S, Ramesar R, Lidral AC, Sommer A, Raposo do Amaral CM, Gorlin RJ, Mulliken JB, Olsen BR. Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet. 2001 Jun;68(6):1321-6. doi: 10.1086/320612. Epub 2001 Apr 16. Citation on PubMed or Free article on PubMed Central
- Tsui HW, Inman RD, Paterson AD, Reveille JD, Tsui FW. ANKH variants associated with ankylosing spondylitis: gender differences. Arthritis Res Ther. 2005;7(3):R513-25. doi: 10.1186/ar1701. Epub 2005 Feb 25. Citation on PubMed or Free article on PubMed Central
- Williams CJ. The role of ANKH in pathologic mineralization of cartilage. Curr Opin Rheumatol. 2016 Mar;28(2):145-51. doi: 10.1097/BOR.0000000000000247. Citation on PubMed
- Zaka R, Williams CJ. Genetics of chondrocalcinosis. Osteoarthritis Cartilage. 2005 Sep;13(9):745-50. doi: 10.1016/j.joca.2005.04.006. Citation on PubMed
- Zaka R, Williams CJ. Role of the progressive ankylosis gene in cartilage mineralization. Curr Opin Rheumatol. 2006 Mar;18(2):181-6. doi: 10.1097/01.bor.0000209432.36355.6e. Citation on PubMed