ANKH Gene

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1		Vicky Zhou	+ 534 word(s)	534	2020-12-15 07:44:27

This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/gene/ankh

ANKH inorganic pyrophosphate transport regulator

genes

1. Normal Function

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.

2. Health Conditions Related to Genetic Changes

2.1. Craniometaphyseal Dysplasia

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.

2.2. Other Disorders

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.

3. Other Names for This Gene

ANK
ANKH_HUMAN
ankylosis, progressive homolog (mouse)
FLJ27166
HANK
MANK
progressive ankylosis protein
SLC62A1

References

Addison WN, Azari F, Sørensen ES, Kaartinen MT, McKee MD. Pyrophosphateinhibits mineralization of osteoblast cultures by binding to mineral,up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J BiolChem. 2007 May 25;282(21):15872-83.
Chen IP, Luxmi R, Kanaujiya J, Hao Z, Reichenberger EJ. CraniometaphysealDysplasia Mutations in ANKH Negatively Affect Human Induced Pluripotent Stem CellDifferentiation into Osteoclasts. Stem Cell Reports. 2017 Nov 14;9(5):1369-1376. doi: 10.1016/j.stemcr.2017.09.016.
Chen IP, Wang L, Jiang X, Aguila HL, Reichenberger EJ. A Phe377del mutation inANK 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.
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.
Korostishevsky M, Vistoropsky Y, Malkin I, Kobyliansky E, Livshits G.Anthropometric and bone-related biochemical factors are associated with differenthaplotypes of ANKH locus. Ann Hum Biol. 2008 Sep-Oct;35(5):535-46. doi:10.1080/03014460802304588.
Malkin I, Dahm S, Suk A, Kobyliansky E, Toliat M, Ruf N, Livshits G, Nürnberg P. Association of ANKH gene polymorphisms with radiographic hand bone size andgeometry in a Chuvasha population. Bone. 2005 Feb;36(2):365-73.
Malkin I, Ermakov S, Kobyliansky E, Livshits G. Strong association betweenpolymorphisms in ANKH locus and skeletal size traits. Hum Genet. 2006Aug;120(1):42-51.
Nürnberg P, Thiele H, Chandler D, Höhne 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 mutationsin ANKH, the human ortholog of the mouse progressive ankylosis gene, result incraniometaphyseal dysplasia. Nat Genet. 2001 May;28(1):37-41.
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 HumGenet. 2002 Oct;71(4):933-40.
Reichenberger E, Chen IP. Craniometaphyseal Dysplasia, Autosomal Dominant.2007 Aug 27 [updated 2020 Jun 11]. In: Adam MP, Ardinger HH, Pagon RA, WallaceSE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle(WA): University of Washington, Seattle; 1993-2020. Available fromhttp://www.ncbi.nlm.nih.gov/books/NBK1461/
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 thetransmembrane protein ANK. Am J Hum Genet. 2001 Jun;68(6):1321-6.
Tsui HW, Inman RD, Paterson AD, Reveille JD, Tsui FW. ANKH variants associatedwith ankylosing spondylitis: gender differences. Arthritis Res Ther.2005;7(3):R513-25.
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. Review.
Zaka R, Williams CJ. Genetics of chondrocalcinosis. Osteoarthritis Cartilage. 2005 Sep;13(9):745-50. Review.
Zaka R, Williams CJ. Role of the progressive ankylosis gene in cartilagemineralization. Curr Opin Rheumatol. 2006 Mar;18(2):181-6. Review.

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Subjects: Genetics & Heredity

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Vicky Zhou

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Entry Collection: MedlinePlus

Update Date: 24 Dec 2020

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