The TUBB4A gene provides instructions for making a protein called beta-tubulin (β-tubulin). This protein is part of the tubulin family of proteins that form and organize structures called microtubules. Microtubules are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). They are composed of β-tubulin and a similar protein called alpha-tubulin (α-tubulin) that is produced from a different gene.
The β-tubulin protein produced from the TUBB4A gene is found primarily in the brain, particularly in regions called the basal ganglia (specifically a part called the putamen) and the cerebellum. These regions help control movement. The protein is also found extensively in the brain's white matter, which consists of nerve fibers covered by a fatty substance called myelin that insulates and protects them. During brain development, microtubules help move nerve cells (neurons) to their proper location (neuronal migration). The microtubules also form scaffolding within neurons that provides structure and aids in the transport of substances.
Health Conditions Related to Genetic Changes
More than 30 mutations in the TUBB4A gene cause TUBB4A-related leukodystrophy. This disorder is characterized by abnormalities of the white matter, particularly a reduced ability of the nervous system to produce myelin (hypomyelination). TUBB4A-related leukodystrophy has a wide range of severity, with a condition called hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) at the most severe end of the spectrum and isolated hypomyelination at the mildest end; the features in some affected individuals fall in between these two extremes. In addition to hypomyelination in certain brain regions, including those that help control movements, affected individuals can have breakdown (atrophy) of brain tissue in these regions, movement abnormalities, difficulty swallowing and speaking, and learning problems.
The mutations that cause TUBB4A-related leukodystrophy change single protein building blocks (amino acids) in the β-tubulin protein. H-ABC is most commonly caused by a mutation that replaces the amino acid aspartate with the amino acid asparagine at protein position 249 (written as Asp249Asn or D249N). This and other TUBB4A gene mutations are thought to alter the structure of the β-tubulin protein, likely impairing the formation or stability of microtubules. While it is unclear how these genetic changes lead to the signs and symptoms of TUBB4A-related leukodystrophy, researchers suspect that problems with microtubules impair neuronal migration or the transport of important substances within neurons, which may lead to dysfunction and loss of these cells in the brain, particularly in the putamen, cerebellum, and white matter. Abnormalities in these brain regions underlie the movement, speech, and learning problems that can occur in TUBB4A-related leukodystrophy. It is unclear what causes the wide range of severity in this disorder.More About This Health Condition
At least two TUBB4A gene mutations have been found to cause another neurological disorder called dystonia 4 (also known as DYT4 dystonia or whispering dysphonia), which is characterized by a weak, whispery voice (dysphonia) that typically begins in adulthood. Affected adults later develop involuntary muscle contractions (dystonia), difficulty walking, and sometimes swallowing problems (dysphagia). Individuals with dystonia 4 do not have hypomyelination or other brain abnormalities like those that occur in people with TUBB4A-related leukodystrophy (described above).
The most common TUBB4A gene mutation that causes dystonia 4 replaces the amino acid arginine with the amino acid glycine at protein position 2 (written as Arg2Gly or R2G). The mutations that cause this condition are thought to disrupt the structure of the β-tubulin protein and, consequently, the formation or stability of microtubules. However, it is unclear how these genetic changes lead to the signs and symptoms of dystonia 4 or why they do not cause hypomyelination like other TUBB4A gene mutations.
Other Names for This Gene
- dystonia 4, torsion (autosomal dominant)
- tubulin beta-4 chain
- tubulin beta-4A chain isoform 1
- tubulin beta-4A chain isoform 2
- tubulin beta-4A chain isoform 3
- tubulin beta-4A chain isoform 4
- tubulin, beta 4
- tubulin, beta, 5
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Hamilton EM, Polder E, Vanderver A, Naidu S, Schiffmann R, Fisher K, Raguž AB, Blumkin L; H-ABC Research Group, van Berkel CG, Waisfisz Q, Simons C, Taft RJ, Abbink TE, Wolf NI, van der Knaap MS. Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation. Brain. 2014 Jul;137(Pt 7):1921-30. doi: 10.1093/brain/awu110. Epub 2014 Apr 30. Citation on PubMed or Free article on PubMed Central
- Hersheson J, Mencacci NE, Davis M, MacDonald N, Trabzuni D, Ryten M, Pittman A, Paudel R, Kara E, Fawcett K, Plagnol V, Bhatia KP, Medlar AJ, Stanescu HC, Hardy J, Kleta R, Wood NW, Houlden H. Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia. Ann Neurol. 2013 Apr;73(4):546-53. doi: 10.1002/ana.23832. Epub 2013 Feb 19. Citation on PubMed or Free article on PubMed Central
- Kancheva D, Chamova T, Guergueltcheva V, Mitev V, Azmanov DN, Kalaydjieva L, Tournev I, Jordanova A. Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia. Mov Disord. 2015 May;30(6):854-8. doi: 10.1002/mds.26196. Epub 2015 Mar 15. Citation on PubMed
- Lohmann K, Wilcox RA, Winkler S, Ramirez A, Rakovic A, Park JS, Arns B, Lohnau T, Groen J, Kasten M, Brüggemann N, Hagenah J, Schmidt A, Kaiser FJ, Kumar KR, Zschiedrich K, Alvarez-Fischer D, Altenmüller E, Ferbert A, Lang AE, Münchau A, Kostic V, Simonyan K, Agzarian M, Ozelius LJ, Langeveld AP, Sue CM, Tijssen MA, Klein C. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene. Ann Neurol. 2013 Apr;73(4):537-45. doi: 10.1002/ana.23829. Epub 2013 Apr 17. Citation on PubMed
- Pizzino A, Pierson TM, Guo Y, Helman G, Fortini S, Guerrero K, Saitta S, Murphy JL, Padiath Q, Xie Y, Hakonarson H, Xu X, Funari T, Fox M, Taft RJ, van der Knaap MS, Bernard G, Schiffmann R, Simons C, Vanderver A. TUBB4A de novo mutations cause isolated hypomyelination. Neurology. 2014 Sep 2;83(10):898-902. doi: 10.1212/WNL.0000000000000754. Epub 2014 Aug 1. Citation on PubMed or Free article on PubMed Central
- Simons C, Wolf NI, McNeil N, Caldovic L, Devaney JM, Takanohashi A, Crawford J, Ru K, Grimmond SM, Miller D, Tonduti D, Schmidt JL, Chudnow RS, van Coster R, Lagae L, Kisler J, Sperner J, van der Knaap MS, Schiffmann R, Taft RJ, Vanderver A. A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. Am J Hum Genet. 2013 May 2;92(5):767-73. doi: 10.1016/j.ajhg.2013.03.018. Epub 2013 Apr 11. Citation on PubMed or Free article on PubMed Central