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Normal Function
The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is necessary for the ubiquitin-proteasome system, which targets damaged or unneeded proteins to be broken down (degraded) within cells. Protein degradation helps maintain the proper balance of protein production and breakdown (protein homeostasis). Old proteins need to be removed to make way for new proteins to allow cells to function and survive. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins.
Ubiquitin-activating enzyme E1 is responsible for the first step in the ubiquitin-proteasome system; it turns on (activates) a small protein called ubiquitin. With the assistance of other proteins, the active ubiquitin attaches to a protein that is to be broken down. When a chain of ubiquitin proteins is attached to a protein, the protein is recognized and destroyed by a complex of enzymes called a proteasome.
Health Conditions Related to Genetic Changes
VEXAS syndrome
Variants (also called mutations) in the UBA1 gene have been found to cause VEXAS syndrome. This condition is characterized by episodes of fever and abnormal inflammation affecting many parts of the body, particularly the skin, joints, and blood vessels. The UBA1 gene variants that cause VEXAS syndrome are somatic, which means that they occur after birth during a person's lifetime. These variants occur only in certain immune cells and blood-forming cells in the bone marrow.
Most cases of VEXAS syndrome are caused by genetic variants that change the protein building block (amino acid) methione at position 41 in the ubiquitin-activating enzyme E1 to another amino acid. These variants lead to the production of an abnormally short enzyme with reduced function. As a result, damaged or unneeded proteins build up inside cells instead of being broken down, which may contribute to abnormal activation of immune cells or cell damage and death. This protein buildup also disrupts protein homeostasis. Old proteins must be removed before cells can make new proteins. If these damaged or unneeded proteins are not broken down, they can impair normal cell functions by stopping the production of new proteins. When UBA1 gene variants occur in immune cells or blood cells, they lead to abnormal inflammation, impaired blood cell development, and other features of VEXAS syndrome.
More About This Health ConditionX-linked infantile spinal muscular atrophy
Variants in the UBA1 gene have been reported to cause X-linked infantile spinal muscular atrophy. This condition is characterized by severe muscle weakness that begins at birth or in early infancy. Weakness in the chest muscles that control breathing often causes death from respiratory failure in early childhood.
UBA1 gene variants that cause X-linked infantile spinal muscular atrophy are inherited and present in all cells in the body. They all change one DNA building block (nucleotide) in an area of the gene known as exon 15. These variants reduce the activity, function, or production of the enzyme. This shortage of functional enzyme allows damaged or unneeded proteins to build up inside cells instead of being broken down, which may damage cells and contribute to cell death. This buildup also disrupts protein homeostasis. If damaged or unneeded proteins are not broken down, they can impair normal cell functions by stopping the production of new proteins. An imbalance in protein production and breakdown can ultimately lead to cell death. Specialized nerve cells that control muscle movement (motor neurons) are particularly susceptible to disruptions in cell function, likely due to their large size. Loss of these cells causes many of the signs and symptoms of X-linked infantile spinal muscular atrophy.
More About This Health ConditionOther Names for This Gene
- GXP1
- SMAX2
- UBA1, ubiquitin-activating enzyme E1 homolog A
- UBA1_HUMAN
- UBA1A
- UBE1
- UBE1X
- ubiquitin-activating enzyme E1
- ubiquitin-like modifier activating enzyme 1
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Balak CD, Hunter JM, Ahearn ME, Wiley D, D'urso G, Baumbach-Reardon L. Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy. F1000Res. 2017 Sep 4;6:1636. doi: 10.12688/f1000research.11878.1. eCollection 2017. Citation on PubMed or Free article on PubMed Central
- Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z, Patel B, Manthiram K, Groarke EM, Gutierrez-Rodrigues F, Hoffmann P, Rosenzweig S, Nakabo S, Dillon LW, Hourigan CS, Tsai WL, Gupta S, Carmona-Rivera C, Asmar AJ, Xu L, Oda H, Goodspeed W, Barron KS, Nehrebecky M, Jones A, Laird RS, Deuitch N, Rowczenio D, Rominger E, Wells KV, Lee CR, Wang W, Trick M, Mullikin J, Wigerblad G, Brooks S, Dell'Orso S, Deng Z, Chae JJ, Dulau-Florea A, Malicdan MCV, Novacic D, Colbert RA, Kaplan MJ, Gadina M, Savic S, Lachmann HJ, Abu-Asab M, Solomon BD, Retterer K, Gahl WA, Burgess SM, Aksentijevich I, Young NS, Calvo KR, Werner A, Kastner DL, Grayson PC. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020 Dec 31;383(27):2628-2638. doi: 10.1056/NEJMoa2026834. Epub 2020 Oct 27. Citation on PubMed
- Georgin-Lavialle S, Terrier B, Guedon AF, Heiblig M, Comont T, Lazaro E, Lacombe V, Terriou L, Ardois S, Bouaziz JD, Mathian A, Le Guenno G, Aouba A, Outh R, Meyer A, Roux-Sauvat M, Ebbo M, Zhao LP, Bigot A, Jamilloux Y, Guillotin V, Flamarion E, Henneton P, Vial G, Jachiet V, Rossignol J, Vinzio S, Weitten T, Vinit J, Deligny C, Humbert S, Samson M, Magy-Bertrand N, Moulinet T, Bourguiba R, Hanslik T, Bachmeyer C, Sebert M, Kostine M, Bienvenu B, Biscay P, Liozon E, Sailler L, Chasset F, Audemard-Verger A, Duroyon E, Sarrabay G, Borlot F, Dieval C, Cluzeau T, Marianetti P, Lobbes H, Boursier G, Gerfaud-Valentin M, Jeannel J, Servettaz A, Audia S, Larue M, Henriot B, Faucher B, Graveleau J, de Sainte Marie B, Galland J, Bouillet L, Arnaud C, Ades L, Carrat F, Hirsch P, Fenaux P, Fain O, Sujobert P, Kosmider O, Mekinian A; French VEXAS group; GFEV, GFM, CEREMAIA, MINHEMON. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol. 2022 Mar;186(3):564-574. doi: 10.1111/bjd.20805. Epub 2021 Nov 28. Citation on PubMed
- Groen EJN, Gillingwater TH. UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration. Trends Mol Med. 2015 Oct;21(10):622-632. doi: 10.1016/j.molmed.2015.08.003. Citation on PubMed or Free article on PubMed Central
- Ramser J, Ahearn ME, Lenski C, Yariz KO, Hellebrand H, von Rhein M, Clark RD, Schmutzler RK, Lichtner P, Hoffman EP, Meindl A, Baumbach-Reardon L. Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy. Am J Hum Genet. 2008 Jan;82(1):188-93. doi: 10.1016/j.ajhg.2007.09.009. Citation on PubMed or Free article on PubMed Central
- Schulman BA, Harper JW. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009 May;10(5):319-31. doi: 10.1038/nrm2673. Epub 2009 Apr 8. Citation on PubMed or Free article on PubMed Central
- Zheng M, Liu J, Yang Z, Gu X, Li F, Lou T, Ji C, Mao Y. Expression, purification and characterization of human ubiquitin-activating enzyme, UBE1. Mol Biol Rep. 2010 Mar;37(3):1413-9. doi: 10.1007/s11033-009-9525-3. Epub 2009 Apr 3. Citation on PubMed
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