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Genetics Home Reference: your guide to understanding genetic conditions
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NOTCH2

Reviewed February 2015

What is the official name of the NOTCH2 gene?

The official name of this gene is “notch 2.”

NOTCH2 is the gene's official symbol. The NOTCH2 gene is also known by other names, listed below.

What is the normal function of the NOTCH2 gene?

The NOTCH2 gene provides instructions for making a protein called Notch2, a member of the Notch family of receptors. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Attachment of a ligand to the Notch2 receptor sends signals that are important for normal development and function of many tissues throughout the body, both before and after birth. In particular, research indicates that Notch2 signaling is important for the development of cells destined to be part of the heart, liver, kidneys, teeth, bones, and other structures in a growing embryo. After birth, Notch2 signaling is involved in immune system function, tissue repair, and a process called bone remodeling, in which old bone is removed and new bone is created to replace it.

The Notch2 receptor has several major parts. A region of the receptor called the extracellular domain extends from the surface of the cell and binds to ligands. This binding triggers the part of the receptor inside the cell, known as the intracellular domain or NICD, to be cut (cleaved) from the rest of the protein. The NICD then moves into the cell's nucleus, where it interacts with other proteins to regulate the activity of specific genes. The very end of the NICD contains a region known as a proline-, glutamic acid-, serine-, and threonine-rich (PEST) domain. The PEST domain is necessary for the NICD to be broken down, which stops Notch2 signaling at the appropriate time.

Does the NOTCH2 gene share characteristics with other genes?

The NOTCH2 gene belongs to a family of genes called ANKRD (ankyrin repeat domain containing).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the NOTCH2 gene related to health conditions?

Alagille syndrome - caused by mutations in the NOTCH2 gene

NOTCH2 gene mutations appear to be a relatively uncommon cause of Alagille syndrome, a condition that can affect the liver, heart, and other parts of the body. At least 10 mutations in the NOTCH2 gene have been associated with the condition. These mutations can affect either the intracellular or extracellular domain of the Notch2 receptor. The genetic changes probably lead to the production of a receptor that is abnormally small or folded into the wrong 3-dimensional shape. These mutations are described as "loss-of-function" because the defective receptor is unable to bind to its ligands and trigger signaling within the cell. Disrupted Notch2 signaling is believed to affect the development of numerous organs and tissues, resulting in the signs and symptoms of Alagille syndrome.

cancers - associated with the NOTCH2 gene

Mutations in the NOTCH2 gene have also been found in certain forms of lymphoma, which is a group of cancers that arise from immune system cells. These mutations are somatic, which means that they are not inherited. Somatic mutations are acquired during a person's lifetime and are present only in certain cells. The NOTCH2 gene mutations associated with lymphomas are described as "gain-of-function" because they increase the activity (expression) of the NOTCH2 gene in certain immune system cells. In some affected cells, extra copies of the mutated gene have been found, further increasing gene activity. Overexpression of this gene may lead to uncontrolled cell growth and cell division in immune system cells, which can result in the development of lymphoma.

Hajdu-Cheney syndrome - associated with the NOTCH2 gene

Several mutations in the NOTCH2 gene have been associated with Hajdu-Cheney syndrome, a rare disorder that can affect many parts of the body, particularly the bones. Affected individuals have acro-osteolysis, which is a loss of bone tissue that affects the hands and feet most severely. Most people with this condition also have osteoporosis, which causes the bones to be brittle and prone to fracture; distinctive facial features; spinal abnormalities; and short stature. Additionally, Hajdu-Cheney syndrome can affect the joints, teeth, heart, kidneys, and other parts of the body.

The mutations associated with Hajdu-Cheney syndrome all occur near the end of the NOTCH2 gene in a region called exon 34. These mutations lead to an abnormally shortened version of the Notch2 receptor that is missing the PEST domain. Without this domain, the receptor cannot be broken down normally, and Notch2 signaling within the cell continues after it should stop. Because the NOTCH2 gene mutations related to Hajdu-Cheney syndrome lead to abnormally increased Notch2 signaling, they are described as "gain-of-function" mutations.

Researchers are unsure how excessive Notch2 signaling is related to the varied features of Hajdu-Cheney syndrome. They suspect that the skeletal features of the disorder, including acro-osteolysis, osteoporosis, and distinctive facial features, likely result from abnormal bone development and remodeling. Excess signaling through the overactive Notch2 receptor may increase the removal of old bone, reduce the formation of new bone, or both. It is less clear how the overactive receptor contributes to the other signs and symptoms of this condition.

Where is the NOTCH2 gene located?

Cytogenetic Location: 1p13-p11

Molecular Location on chromosome 1: base pairs 119,911,552 to 120,069,702

The NOTCH2 gene is located on the short (p) arm of chromosome 1 between positions 13 and 11.

The NOTCH2 gene is located on the short (p) arm of chromosome 1 between positions 13 and 11.

More precisely, the NOTCH2 gene is located from base pair 119,911,552 to base pair 120,069,702 on chromosome 1.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about NOTCH2?

You and your healthcare professional may find the following resources about NOTCH2 helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the NOTCH2 gene or gene products?

  • hN2
  • NOTC2_HUMAN
  • notch 2 preproprotein
  • Notch (Drosophila) homolog 2
  • Notch homolog 2 (Drosophila)

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding NOTCH2?

bone remodeling ; cell ; cell division ; domain ; embryo ; exon ; extracellular ; gene ; glutamic acid ; immune system ; inherited ; intracellular ; ligand ; lymphoma ; nucleus ; osteoporosis ; proline ; protein ; receptor ; serine ; short stature ; stature ; syndrome ; threonine ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References

  • Gene Review: Alagille Syndrome (http://www.ncbi.nlm.nih.gov/books/NBK1273)
  • Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet. 2011 Mar 6;43(4):306-8. doi: 10.1038/ng.778. (http://www.ncbi.nlm.nih.gov/pubmed/21378989?dopt=Abstract)
  • Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G, Nannya Y, Suzuki R, Ota S, Ota Y, Izutsu K, Sakata-Yanagimoto M, Hangaishi A, Yagita H, Fukayama M, Seto M, Kurokawa M, Ogawa S, Chiba S. Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci. 2009 May;100(5):920-6. (http://www.ncbi.nlm.nih.gov/pubmed/19445024?dopt=Abstract)
  • Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, Boycott KM, Ste-Marie LG, McKiernan FE, Marik I, Van Esch H; FORGE Canada Consortium, Michaud JL, Samuels ME. Mutations in NOTCH2 in families with Hajdu-Cheney syndrome. Hum Mutat. 2011 Oct;32(10):1114-7. doi: 10.1002/humu.21546. Epub 2011 Sep 9. (http://www.ncbi.nlm.nih.gov/pubmed/21681853?dopt=Abstract)
  • McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. 2006 Jul;79(1):169-73. Epub 2006 May 10. (http://www.ncbi.nlm.nih.gov/pubmed/16773578?dopt=Abstract)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/4853)
  • OMIM: NOTCH, DROSOPHILA, HOMOLOG OF, 2 (http://omim.org/entry/600275)
  • Penton AL, Leonard LD, Spinner NB. Notch signaling in human development and disease. Semin Cell Dev Biol. 2012 Jun;23(4):450-7. doi: 10.1016/j.semcdb.2012.01.010. Epub 2012 Jan 28. Review. (http://www.ncbi.nlm.nih.gov/pubmed/22306179?dopt=Abstract)
  • Trøen G, Wlodarska I, Warsame A, Hernández Llodrà S, De Wolf-Peeters C, Delabie J. NOTCH2 mutations in marginal zone lymphoma. Haematologica. 2008 Jul;93(7):1107-9. doi: 10.3324/haematol.11635. Epub 2008 May 27. (http://www.ncbi.nlm.nih.gov/pubmed/18508802?dopt=Abstract)
  • Varadkar P, Kraman M, Despres D, Ma G, Lozier J, McCright B. Notch2 is required for the proliferation of cardiac neural crest-derived smooth muscle cells. Dev Dyn. 2008 Apr;237(4):1144-52. doi: 10.1002/dvdy.21502. (http://www.ncbi.nlm.nih.gov/pubmed/18330927?dopt=Abstract)
  • Zanotti S, Canalis E. Notch signaling in skeletal health and disease. Eur J Endocrinol. 2013 May 8;168(6):R95-103. doi: 10.1530/EJE-13-0115. Print 2013 Jun. Review. (http://www.ncbi.nlm.nih.gov/pubmed/23554451?dopt=Abstract)
  • Zhao W, Petit E, Gafni RI, Collins MT, Robey PG, Seton M, Miller KK, Mannstadt M. Mutations in NOTCH2 in patients with Hajdu-Cheney syndrome. Osteoporos Int. 2013 Aug;24(8):2275-81. doi: 10.1007/s00198-013-2298-5. Epub 2013 Feb 7. (http://www.ncbi.nlm.nih.gov/pubmed/23389697?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2015
Published: June 29, 2015