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URL of this page: https://medlineplus.gov/genetics/gene/notch2/

NOTCH2 gene

notch receptor 2

Normal Function

The NOTCH2 gene provides instructions for making a protein that belongs to a large family of receptor proteins. Other proteins, called ligands, can fit into specific sites on receptor proteins, like a key into a lock. When a ligand attaches to the NOTCH2 receptor protein, it triggers a signaling pathway that is important for normal growth and development. Before birth, NOTCH2 signaling plays a role in the development of cells that will become part of the heart, liver, kidneys, teeth, bones, and other structures in the 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. NOTCH2 signaling also plays a role in the communication between neighboring cells.

The NOTCH2 receptor protein is embedded in the cell membrane and has several major parts, including a region that extends outward from the surface of the cell and a region that lies inside the cell. When a ligand binds to the outer portion of the NOTCH2 receptor protein, the inner portion separates from the rest of the protein. This part of the protein travels into the cell's nucleus, where it helps regulate the activity of specific genes.

Health Conditions Related to Genetic Changes

Alagille syndrome

Variants (also called mutations) in the NOTCH2 gene are a relatively uncommon cause of Alagille syndrome, a condition that can affect the liver, heart, and other parts of the body. Many of the variants in the NOTCH2 gene that cause Alagille syndrome lead to the substitution of one protein building block (amino acid) for another in the NOTCH2 receptor protein, which likely impairs NOTCH2 signaling. Disrupted NOTCH2 signaling is believed to affect the development of numerous organs and tissues, which leads to the signs and symptoms of Alagille syndrome.

More About This Health Condition

Hajdu-Cheney syndrome

Several variants 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 acroosteolysis, which is a loss of bone tissue that mostly affects the fingers and toes. Additional signs and symptoms include osteoporosis, which causes the bones to be brittle and prone to fracture; distinctive facial features; spinal abnormalities; and short stature. 

The variants that are associated with Hajdu-Cheney syndrome occur near the end of the NOTCH2 gene and cause cells to produce a version of the NOTCH2 receptor protein that cannot be broken down properly. As a result, the protein accumulates, which leads to an increase in NOTCH2 signaling. These variants are described as "gain-of-function variants."

Researchers are unsure exactly how this buildup of NOTCH2 receptor protein leads to the various features of Hajdu-Cheney syndrome. They suspect that the skeletal features of the disorder are a result of abnormal bone development and remodeling.

More About This Health Condition

Cancers

Certain variants in the NOTCH2 gene have also been found in people with various types of cancers, including those of the blood, liver, stomach, and bladder. These cancer-causing variants are somatic, which means that they are not inherited and are present only in certain cells. Many of the NOTCH2 gene variants that are associated with cancer lead to a disruption in NOTCH2 signaling, which contributes to the uncontrolled growth and division that is characteristic of cancer cells. 

Other disorders

A variant in the NOTCH2 gene has also been found to cause skeletal fragility, a condition in which the bones are weaker than usual and prone to fracture. This NOTCH2 gene variant leads to changes in the NOTCH2 receptor protein that disrupt its activation and impair NOTCH2 signaling. As a result, bone remodeling is impaired, leading to skeletal fragility.

Other Names for This Gene

  • hN2
  • notch 2

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

  • Abdelkarim M, Alageel D, Ahsan F, Alhuthil R, Alsarhani H, Alsagheir A. Hajdu-Cheney syndrome with a novel variant in NOTCH2 gene: A case report. Bone Rep. 2023 Aug 18;19:101709. doi: 10.1016/j.bonr.2023.101709. eCollection 2023 Dec. Citation on PubMed
  • Canalis E, Yu J, Denker E, Schilling L, Deymier A, Hao B, Carpenter T. A novel variant of NOTCH2 causes skeletal fragility. Bone. 2026 Jan;202:117702. doi: 10.1016/j.bone.2025.117702. Epub 2025 Nov 2. Citation on PubMed
  • Canalis E. Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism. 2018 Mar;80:48-56. doi: 10.1016/j.metabol.2017.08.002. Epub 2017 Aug 24. Citation on PubMed
  • Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G, McEldrew D, Nassur JA, Rand EB, Krock BL, Kamath BM, Krantz ID, Piccoli DA, Loomes KM, Spinner NB. Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019 Dec;40(12):2197-2220. doi: 10.1002/humu.23879. Epub 2019 Aug 26. Citation on PubMed
  • Isidor B, Lindenbaum P, Pichon O, Bezieau 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. Citation on PubMed
  • 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. Citation on PubMed
  • 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. doi: 10.1086/505332. Epub 2006 May 10. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed or Free article on PubMed Central
  • Shi Q, Xue C, Zeng Y, Yuan X, Chu Q, Jiang S, Wang J, Zhang Y, Zhu D, Li L. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct Target Ther. 2024 May 27;9(1):128. doi: 10.1038/s41392-024-01828-x. Citation on PubMed
  • Spinner NB, Loomes KM, Krantz ID, Gilbert MA. Alagille Syndrome. 2000 May 19 [updated 2024 Jan 4]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1273/ Citation on PubMed
  • 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. Citation on PubMed
  • Xiu MX, Liu YM. The role of oncogenic Notch2 signaling in cancer: a novel therapeutic target. Am J Cancer Res. 2019 May 1;9(5):837-854. eCollection 2019. Citation on PubMed
  • 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. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed or Free article on PubMed Central

The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.