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Normal Function
The TBC1D20 gene provides instructions for making a protein that helps regulate the activity of other proteins called GTPases, which control a variety of functions in cells. Often referred to as molecular switches, GTPases can be turned on and off. They are turned on (active) when they are attached (bound) to a molecule called GTP and are turned off (inactive) when they are bound to another molecule called GDP. The TBC1D20 protein turns off a GTPase known as RAB18 by stimulating a reaction that turns the attached GTP into GDP. When active, RAB18 is involved in a process called vesicle trafficking, which moves proteins and other molecules within cells in sac-like structures called vesicles. RAB18 regulates the movement of substances between compartments in cells and the storage and release of fats (lipids) by structures called lipid droplets. The protein also appears to play a role in a process called autophagy, which helps clear unneeded materials from cells. RAB18 is important for the organization of a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport.
The TBC1D20 protein is also thought to inactivate another GTPase called RAB1. RAB1 is important for maintaining the structure of a cell compartment called the Golgi apparatus, in which newly produced proteins are modified so they can carry out their functions. The TBC1D20 protein also appears to play a role in the copying (replication) of viruses in infected cells.
Health Conditions Related to Genetic Changes
RAB18 deficiency
At least five mutations in the TBC1D20 gene have been found to cause Warburg micro syndrome, which is the most severe of the disorders caused by RAB18 deficiency. Warburg micro syndrome is characterized by multiple eye abnormalities, vision impairment, severe intellectual disability, and a reduction of the hormones that direct sexual development (hypogonadotropic hypogonadism).
The TBC1D20 gene mutations that cause Warburg micro syndrome eliminate the function of the TBC1D20 protein. Researchers suspect that loss of this protein's function disrupts the normal control of RAB18 activity. It is unclear, though, how the resulting changes in RAB18 activity might lead to eye problems, brain abnormalities, and other features of Warburg micro syndrome.
Because Warburg micro syndrome can be caused by mutations in other genes that disrupt normal RAB18 activity, loss of control of this GTPase is thought to underlie the condition. It is unclear if impaired regulation of RAB1 activity contributes to the features of the condition.
More About This Health ConditionOther Names for This Gene
- C20orf140
- dJ852M4.2
- WARBM4
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Feldmann A, Bekbulat F, Huesmann H, Ulbrich S, Tatzelt J, Behl C, Kern A. The RAB GTPase RAB18 modulates macroautophagy and proteostasis. Biochem Biophys Res Commun. 2017 May 6;486(3):738-743. doi: 10.1016/j.bbrc.2017.03.112. Epub 2017 Mar 22. Citation on PubMed
- Gerondopoulos A, Bastos RN, Yoshimura S, Anderson R, Carpanini S, Aligianis I, Handley MT, Barr FA. Rab18 and a Rab18 GEF complex are required for normal ER structure. J Cell Biol. 2014 Jun 9;205(5):707-20. doi: 10.1083/jcb.201403026. Epub 2014 Jun 2. Citation on PubMed or Free article on PubMed Central
- Haas AK, Yoshimura S, Stephens DJ, Preisinger C, Fuchs E, Barr FA. Analysis of GTPase-activating proteins: Rab1 and Rab43 are key Rabs required to maintain a functional Golgi complex in human cells. J Cell Sci. 2007 Sep 1;120(Pt 17):2997-3010. doi: 10.1242/jcs.014225. Epub 2007 Aug 7. Citation on PubMed
- Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, Linford A, Chang B, Morris-Rosendahl DJ, Carpanini S, Posmyk R, Harthill V, Sheridan E, Abdel-Salam GM, Terhal PA, Faravelli F, Accorsi P, Giordano L, Pinelli L, Hartmann B, Ebert AD, Barr FA, Aligianis IA, Sidjanin DJ. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013 Dec 5;93(6):1001-14. doi: 10.1016/j.ajhg.2013.10.011. Epub 2013 Nov 14. Citation on PubMed or Free article on PubMed Central
- Nachmias D, Sklan EH, Ehrlich M, Bacharach E. Human immunodeficiency virus type 1 envelope proteins traffic toward virion assembly sites via a TBC1D20/Rab1-regulated pathway. Retrovirology. 2012 Jan 19;9:7. doi: 10.1186/1742-4690-9-7. Citation on PubMed or Free article on PubMed Central
- Sklan EH, Serrano RL, Einav S, Pfeffer SR, Lambright DG, Glenn JS. TBC1D20 is a Rab1 GTPase-activating protein that mediates hepatitis C virus replication. J Biol Chem. 2007 Dec 14;282(50):36354-61. doi: 10.1074/jbc.M705221200. Epub 2007 Sep 27. Citation on PubMed
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