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URL of this page: https://medlineplus.gov/genetics/gene/serpini1/

SERPINI1 gene

serpin family I member 1

Normal Function

The SERPINI1 gene provides instructions for making a protein called neuroserpin, which is a type of serine protease inhibitor (serpin). Serpins help control several kinds of chemical reactions by blocking (inhibiting) the activity of certain proteins. Neuroserpin inhibits the activity of an enzyme called tissue plasminogen activator (tPA), which plays a role in cell movement (migration), blood clotting, and inflammation.

By inhibiting tPA activity, neuroserpin is involved in the development and function of the nervous system. Neuroserpin helps nerve cells (neurons) divide and mature so they can take on specific functions (differentiation). Neuroserpin also plays a role in the development of synapses, which are the connections between neurons where cell-to-cell communication occurs. Synapses can change and adapt over time in response to experience, a characteristic called synaptic plasticity. Neuroserpin helps regulate synaptic plasticity, which suggests that it may be important for learning and memory.

Health Conditions Related to Genetic Changes

Familial encephalopathy with neuroserpin inclusion bodies

Variants (also called mutations) in the SERPINI1 gene have been found to cause familial encephalopathy with neuroserpin inclusion bodies (FENIB). This condition causes progressive dysfunction of the brain (encephalopathy), leading to a loss of intellectual functioning (dementia) and seizures. Affected individuals typically have seizures that involve sudden, involuntary muscle jerking or twitching (myoclonus).

Variants in the SERPINI1 gene can lead to single protein building blocks (amino acids) being substituted for others in the neuroserpin protein. These changes cause cells to produce abnormally shaped, unstable versions of neuroserpin. Within neurons, the altered neuroserpin proteins can attach to one another and form chains (neuroserpin polymers) that clump together to form neuroserpin inclusion bodies. These inclusion bodies occur in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport. The formation of neuroserpin polymers triggers a stress response in the endoplasmic reticulum that is communicated to other cell structures and ultimately leads to cell death. The gradual loss of neurons in certain parts of the brain causes progressive dementia and other features of FENIB.

Additionally, the formation of neuroserpin polymers likely results in the abnormal release of calcium ions from the endoplasmic reticulum into the cell. This can lead to certain neurons becoming more active than usual, which may trigger the abnormal brain activity that is associated with seizures in people with FENIB.

SERPINI1 gene variants also reduce or eliminate neuroserpin's ability to inhibit tPA in neurons. Researchers believe that unchecked tPA activity may also contribute to the signs and symptoms of FENIB.

Some SERPINI1 gene variants cause more severe forms of FENIB than others. Certain factors can influence the age at which FENIB symptoms appear and the severity of the disease. These factors include how easily the abnormal neuroserpin protein forms neuroserpin polymers and the number of inclusion bodies that form within neurons. The easier it is for neuroserpin polymers to accumulate within neurons, the earlier the neurological problems appear and the more severe they are likely to be. Additionally, people with severe FENIB tend to have more widespread neuron loss than those with milder cases of FENIB.

More About This Health Condition

Other Names for This Gene

  • Axonin-2
  • neuroserpin
  • NEUS_HUMAN
  • PI12
  • Protease inhibitor 12
  • Serpin I1

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

  • Belorgey D, Crowther DC, Mahadeva R, Lomas DA. Mutant Neuroserpin (S49P) that causes familial encephalopathy with neuroserpin inclusion bodies is a poor proteinase inhibitor and readily forms polymers in vitro. J Biol Chem. 2002 May 10;277(19):17367-73. doi: 10.1074/jbc.M200680200. Epub 2002 Mar 5. Citation on PubMed
  • Belorgey D, Sharp LK, Crowther DC, Onda M, Johansson J, Lomas DA. Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB. Eur J Biochem. 2004 Aug;271(16):3360-7. doi: 10.1111/j.1432-1033.2004.04270.x. Citation on PubMed
  • Coutelier M, Andries S, Ghariani S, Dan B, Duyckaerts C, van Rijckevorsel K, Raftopoulos C, Deconinck N, Sonderegger P, Scaravilli F, Vikkula M, Godfraind C. Neuroserpin mutation causes electrical status epilepticus of slow-wave sleep. Neurology. 2008 Jul 1;71(1):64-6. doi: 10.1212/01.wnl.0000316306.08751.28. No abstract available. Citation on PubMed
  • D'Acunto E, Fra A, Visentin C, Manno M, Ricagno S, Galliciotti G, Miranda E. Neuroserpin: structure, function, physiology and pathology. Cell Mol Life Sci. 2021 Oct;78(19-20):6409-6430. doi: 10.1007/s00018-021-03907-6. Epub 2021 Aug 17. Citation on PubMed
  • Davis RL, Holohan PD, Shrimpton AE, Tatum AH, Daucher J, Collins GH, Todd R, Bradshaw C, Kent P, Feiglin D, Rosenbaum A, Yerby MS, Shaw CM, Lacbawan F, Lawrence DA. Familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 1999 Dec;155(6):1901-13. doi: 10.1016/S0002-9440(10)65510-1. Citation on PubMed or Free article on PubMed Central
  • Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, Sonderegger P, Kinter J, Becker LM, Lacbawan F, Krasnewich D, Muenke M, Lawrence DA, Yerby MS, Shaw CM, Gooptu B, Elliott PR, Finch JT, Carrell RW, Lomas DA. Familial dementia caused by polymerization of mutant neuroserpin. Nature. 1999 Sep 23;401(6751):376-9. doi: 10.1038/43894. Citation on PubMed
  • Galliciotti G, Glatzel M, Kinter J, Kozlov SV, Cinelli P, Rulicke T, Sonderegger P. Accumulation of mutant neuroserpin precedes development of clinical symptoms in familial encephalopathy with neuroserpin inclusion bodies. Am J Pathol. 2007 Apr;170(4):1305-13. doi: 10.2353/ajpath.2007.060910. Citation on PubMed or Free article on PubMed Central
  • Galliciotti G, Sonderegger P. Neuroserpin. Front Biosci. 2006 Jan 1;11:33-45. doi: 10.2741/1778. Citation on PubMed
  • Godinez A, Rajput R, Chitranshi N, Gupta V, Basavarajappa D, Sharma S, You Y, Pushpitha K, Dhiman K, Mirzaei M, Graham S, Gupta V. Neuroserpin, a crucial regulator for axogenesis, synaptic modelling and cell-cell interactions in the pathophysiology of neurological disease. Cell Mol Life Sci. 2022 Mar 4;79(3):172. doi: 10.1007/s00018-022-04185-6. Citation on PubMed
  • Hagen MC, Murrell JR, Delisle MB, Andermann E, Andermann F, Guiot MC, Ghetti B. Encephalopathy with neuroserpin inclusion bodies presenting as progressive myoclonus epilepsy and associated with a novel mutation in the Proteinase Inhibitor 12 gene. Brain Pathol. 2011 Sep;21(5):575-82. doi: 10.1111/j.1750-3639.2011.00481.x. Epub 2011 Mar 24. Citation on PubMed
  • Miranda E, Lomas DA. Neuroserpin: a serpin to think about. Cell Mol Life Sci. 2006 Mar;63(6):709-22. doi: 10.1007/s00018-005-5077-4. Citation on PubMed
  • Miranda E, MacLeod I, Davies MJ, Perez J, Romisch K, Crowther DC, Lomas DA. The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB. Hum Mol Genet. 2008 Jun 1;17(11):1527-39. doi: 10.1093/hmg/ddn041. Epub 2008 Feb 11. Citation on PubMed or Free article on PubMed Central
  • Miranda E, Romisch K, Lomas DA. Mutants of neuroserpin that cause dementia accumulate as polymers within the endoplasmic reticulum. J Biol Chem. 2004 Jul 2;279(27):28283-91. doi: 10.1074/jbc.M313166200. Epub 2004 Apr 16. Citation on PubMed
  • Onda M, Belorgey D, Sharp LK, Lomas DA. Latent S49P neuroserpin forms polymers in the dementia familial encephalopathy with neuroserpin inclusion bodies. J Biol Chem. 2005 Apr 8;280(14):13735-41. doi: 10.1074/jbc.M413282200. Epub 2005 Jan 21. Citation on PubMed
  • Yang X, Fang Z, Yan L, He X, Luo H, Han Z, Gui J, Cheng M, Jiang L. Role of SERPINI1 pathogenic variants in familial encephalopathy with neuroserpin inclusion bodies: A case report and literature review. Seizure. 2022 Dec;103:137-147. doi: 10.1016/j.seizure.2022.11.008. Epub 2022 Nov 13. Citation on PubMed
  • Yepes M, Lawrence DA. Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. Thromb Haemost. 2004 Mar;91(3):457-64. doi: 10.1160/TH03-12-0766. Citation on PubMed

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.