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URL of this page: https://medlineplus.gov/genetics/gene/notch3/

NOTCH3 gene

notch receptor 3

Normal Function

The NOTCH3 gene provides instructions for making a receptor protein. Because this protein helps cells communicate with each other, it is positioned across the cell membrane. One end (the intracellular end) remains inside the cell. The receptor's middle (transmembrane) section spans the cell membrane, while its other end (the extracellular end) projects from the outer surface of the cell. The NOTCH3 receptor is found mainly in vascular smooth muscle cells, which are the most common type of cell in most blood vessels. These cells help regulate blood flow by allowing blood vessels to expand and contract.

The NOTCH3 receptor is called a receptor protein because certain other proteins, called ligands, bind to the extracellular end of NOTCH3, fitting like a key into a lock. This binding causes the NOTCH3 intracellular domain to detach. The detached piece enters the nuclei of vascular smooth muscle cells and helps control the activity (transcription) of other genes.

The NOTCH3 receptor is especially important for the normal function of vascular smooth muscle cells and the development and maintenance of blood vessels, including those that supply blood to the brain.

Health Conditions Related to Genetic Changes

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Genetic changes that cause disease are called pathogenic variants. A pathogenic variant in one copy of the NOTCH3 gene can cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, commonly known as CADASIL. CADASIL is a condition that affects the flow of blood in small vessels called arteries, especially the arteries of the brain. CADASIL typically begins in adulthood and can cause strokes, cognitive decline, and changes in mood and behavior.

Most of the pathogenic variants in the NOTCH3 gene that cause CADASIL change a single protein building block (amino acid) in the NOTCH3 receptor. In most cases, the change adds or deletes an amino acid called cysteine in a certain area of the NOTCH3 receptor’s extracellular domain. This change likely prevents the receptor from folding properly, which may impair its function. This change may also cause the protein to take on a form that is harmful to the cell.

The extracellular domains of the altered NOTCH3 receptors form clumps (aggregates) within vascular smooth muscle cells. Through a process that is not well-understood, this leads to the breakdown of vascular smooth muscle cells and a thickening of the blood vessel walls, which impairs normal blood flow in the small arteries of the brain. These changes lead to the strokes, cognitive decline, and other signs and symptoms seen in people with CADASIL.

More About This Health Condition

Lateral meningocele syndrome

Pathogenic variants in the NOTCH3 gene can also cause lateral meningocele syndrome. This disorder affects the nervous system, bones, and muscles and is characterized by abnormalities known as lateral meningoceles. The membranes that surround the spinal cord (meninges) can protrude through gaps in the bones of the spine, forming lateral meningoceles. The protrusions are most common and typically larger in the lower spine. The meningoceles associated with this disorder may damage the nerves that spread from the spine to the rest of the body.

The pathogenic variants that cause lateral meningocele syndrome occur in one copy of the NOTCH3 gene in a region known as exon 33. Most of these changes result in an abnormally short (truncated) version of the NOTCH3 receptor. The shortened receptor is missing the portion that normally causes it to break down when it is no longer needed. As a result, the receptor is overactive and continues to affect the activity of other genes. However, the exact mechanism by which pathogenic variants in the NOTCH3 gene cause lateral meningocele syndrome is not well-understood.

More About This Health Condition

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

MedlinePlus Genetics provides information about Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy

More About This Health Condition

Familial partial lipodystrophy

MedlinePlus Genetics provides information about Familial partial lipodystrophy

More About This Health Condition

Other Names for This Gene

  • CASIL

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

  • Al-Amrani F, Al-Maawali A, Al-Thihli K, Al-Ajmi E, Ganesh A, Al Futaisi A. Autosomal Recessive NOTCH3-Related Leukodystrophy in Two Siblings and Review of the Literature. Pediatr Neurol. 2023 Nov;148:73-80. doi: 10.1016/j.pediatrneurol.2023.07.007. Epub 2023 Jul 16. Citation on PubMed
  • Arboleda-Velasquez JF, Zhou Z, Shin HK, Louvi A, Kim HH, Savitz SI, Liao JK, Salomone S, Ayata C, Moskowitz MA, Artavanis-Tsakonas S. Linking Notch signaling to ischemic stroke. Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4856-61. doi: 10.1073/pnas.0709867105. Epub 2008 Mar 17. Citation on PubMed or Free article on PubMed Central
  • Coupland K, Lendahl U, Karlstrom H. Role of NOTCH3 Mutations in the Cerebral Small Vessel Disease Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy. Stroke. 2018 Nov;49(11):2793-2800. doi: 10.1161/STROKEAHA.118.021560. No abstract available. Citation on PubMed
  • Cramer J, Lui F, White ML. Cerebral Autosomal Dominant Arteriopathy. 2024 Mar 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK470293/ Citation on PubMed
  • Ejaz R, Carter M, Gripp K. NOTCH3-Related Lateral Meningocele Syndrome. 2016 Jun 23 [updated 2022 May 5]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK368476/ Citation on PubMed
  • Felix-Ilemhenbhio F, Kocsy K, Azzouz M, Majid A. The role of NOTCH3 in CADASIL pathogenesis: insights into novel therapies. Brain Res. 2025 Sep 15;1863:149754. doi: 10.1016/j.brainres.2025.149754. Epub 2025 May 31. Citation on PubMed
  • Garg A, Xing C, Agarwal AK, Westfall AK, Tomchick DR, Zhang X, Xing M, Brown RJ. Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways. Diabetes. 2025 Mar 1;74(3):427-438. doi: 10.2337/db24-0624. Citation on PubMed
  • Gripp KW, Robbins KM, Sobreira NL, Witmer PD, Bird LM, Avela K, Makitie O, Alves D, Hogue JS, Zackai EH, Doheny KF, Stabley DL, Sol-Church K. Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. Am J Med Genet A. 2015 Feb;167A(2):271-81. doi: 10.1002/ajmg.a.36863. Epub 2014 Nov 13. Citation on PubMed
  • Hack RJ, Rutten J, Lesnik Oberstein SAJ. CADASIL. 2000 Mar 15 [updated 2019 Mar 14]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1500/ Citation on PubMed
  • Hosseini-Alghaderi S, Baron M. Notch3 in Development, Health and Disease. Biomolecules. 2020 Mar 23;10(3):485. doi: 10.3390/biom10030485. Citation on PubMed
  • Iruzubieta P, Alves CAPF, Al Shamsi AM, ElGhazali G, Zaki MS, Pinelli L, Lopergolo D, Cho BPH, Jolly AA, Al Futaisi A, Al-Amrani F, Galli J, Fazzi E, Vulin K, Barajas-Olmos F, Hengel H, Aljamal BM, Nasr V, Assarzadegan F, Ragno M, Trojano L, Ojeda NM, Cakar A, Bianchi S, Pescini F, Poggesi A, Al Tenalji A, Aziz M, Mohammad R, Chedrawi A, De Stefano N, Zifarelli G, Schols L, Haack TB, Rebelo A, Zuchner S, Koc F, Griffiths LR, Orozco L, Helmes KG, Babaei M, Bauer P, Chan Jeong W, Karimiani EG, Schmidts M, Gleeson JG, Chung WK, Alkuraya FS, Shalbafan B, Markus HS, Houlden H, Maroofian R. Clinical and neuroradiological spectrum of biallelic variants in NOTCH3. EBioMedicine. 2024 Sep;107:105297. doi: 10.1016/j.ebiom.2024.105297. Epub 2024 Aug 26. Citation on PubMed
  • Kalaria RN, Viitanen M, Kalimo H, Dichgans M, Tabira T; CADASIL Group of Vas-Cog. The pathogenesis of CADASIL: an update. J Neurol Sci. 2004 Nov 15;226(1-2):35-9. doi: 10.1016/j.jns.2004.09.008. Citation on PubMed
  • Mizuno T, Mizuta I, Watanabe-Hosomi A, Mukai M, Koizumi T. Clinical and Genetic Aspects of CADASIL. Front Aging Neurosci. 2020 May 7;12:91. doi: 10.3389/fnagi.2020.00091. eCollection 2020. Citation on PubMed
  • Rutten JW, Haan J, Terwindt GM, van Duinen SG, Boon EM, Lesnik Oberstein SA. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. doi: 10.1586/14737159.2014.922880. Citation on PubMed
  • Stellingwerff MD, Nulton C, Helman G, Roosendaal SD, Benko WS, Pizzino A, Bugiani M, Vanderver A, Simons C, van der Knaap MS. Early-Onset Vascular Leukoencephalopathy Caused by Bi-Allelic NOTCH3 Variants. Neuropediatrics. 2022 Apr;53(2):115-121. doi: 10.1055/a-1739-2722. Epub 2022 Feb 23. Citation on PubMed
  • Tasharrofi B, Najafi A, Pourbakhtyaran E, Amirsalari S, Khan GS, Ashrafi MR, Tavasoli AR, Keramatipour M, Heidari M. Distinct neurological phenotypes associated with biallelic loss of NOTCH3 function: evidence for recessive inheritance. Mol Biol Rep. 2024 Jun 1;51(1):714. doi: 10.1007/s11033-024-09560-z. Citation on PubMed
  • Wang MM. CADASIL. Handb Clin Neurol. 2018;148:733-743. doi: 10.1016/B978-0-444-64076-5.00047-8. Citation on PubMed

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