The ARX gene provides instructions for producing a protein that regulates the activity of other genes. On the basis of this action, the ARX protein is called a transcription factor. The ARX gene is part of a larger family of homeobox genes, which act during early embryonic development to control the formation of many body structures. Specifically, the ARX protein is believed to be involved in the development of the brain, pancreas, testes, and muscles used for movement (skeletal muscles).
In the pancreas, testes, and skeletal muscles, the ARX protein helps to regulate the process by which cells mature to carry out specific functions (differentiation). Within the developing brain, the ARX protein is involved with movement (migration) and communication of nerve cells (neurons). In particular, this protein regulates genes that play a role in the migration of specialized neurons (interneurons) to their proper location. Interneurons relay signals between other neurons.
Health Conditions Related to Genetic Changes
Developmental and epileptic encephalopathy 1
Mutations in the ARX gene can cause developmental and epileptic encephalopathy 1 (DEE1), a disorder characterized by recurrent seizures called infantile spasms that begin in the first year of life. Children with this condition also have intellectual disability.
The normal ARX protein contains four regions where a protein building block (amino acid) called alanine is repeated multiple times. These stretches of alanines are known as polyalanine tracts. The most common ARX gene mutations that cause DEE1 add extra alanines to the first or second polyalanine tract in the ARX protein. This type of mutation is called a polyalanine repeat expansion. Research suggests that these polyalanine repeat expansions reduce the amount of ARX protein in cells, although the mechanism is unclear. Other ARX gene mutations that cause this condition are believed to reduce the function of the ARX protein. A shortage of ARX function is thought to impair the normal development and migration of certain interneurons, which likely underlies infantile spasms and other neurological problems characteristic of DEE1.More About This Health Condition
A few mutations in the ARX gene have been identified in people with Partington syndrome, a neurological disorder that causes intellectual disability and a group of movement problems called focal dystonia that primarily affects the hands. The most common mutation that causes Partington syndrome, a duplication of genetic material written as c.428_451dup, adds extra alanines to the second polyalanine tract in the ARX protein. The polyalanine repeat expansion likely reduces the amount of ARX protein or impairs its function and may disrupt normal interneuron migration in the developing brain, leading to the intellectual disability and dystonia characteristic of Partington syndrome.More About This Health Condition
X-linked lissencephaly with abnormal genitalia
At least 30 mutations in the ARX gene can cause X-linked lissencephaly with abnormal genitalia (XLAG). This condition is characterized by abnormal brain development that results in the brain having a smooth appearance (lissencephaly) instead of its normal folds and grooves. Males with XLAG also have abnormal genitalia. The ARX gene mutations that cause XLAG lead to the production of a nonfunctional ARX protein or to a complete absence of ARX protein. As a result, the ARX protein cannot perform its role regulating the activity of genes important for interneuron migration. In addition to impairing normal brain development, a lack of functional ARX protein disrupts cell differentiation in the testes, leading to the development of abnormal genitalia. It is thought that the disruption of ARX protein function in the pancreas plays a role in digestive issues, including chronic diarrhea, experienced by individuals with XLAG.
Females with an ARX gene mutation typically have less severe signs and symptoms than males. Affected females may have an absence of the tissue connecting the left and right halves of the brain (agenesis of the corpus callosum), some degree of intellectual disability, and recurrent seizures (epilepsy). Some females with an ARX gene mutation experience no symptoms.More About This Health Condition
Mutations in the ARX gene can cause a variety of conditions that impair brain function. Some ARX gene mutations result in intellectual disability without other neurological problems. Because the ARX gene is on the X chromosome, this condition is known as X-linked intellectual disability (XLID) or sometimes nonsyndromic XLID. XLID can occur in combination with other neurological problems as part of distinct conditions called XLID syndromes. ARX gene mutations account for 9.5 percent of all cases of XLID.
ARX gene mutations cause several XLID syndromes, including X-linked lissencephaly with abnormal genitalia, early infantile epileptic encephalopathy 1, and Partington syndrome (described above). Another is X-linked myoclonic epilepsy with intellectual disability and spasticity, which causes intellectual disability and epilepsy. ARX gene mutations also cause several syndromes that include structural brain malformations. These include Proud syndrome, which is characterized by agenesis of the corpus callosum as well as abnormal male genitalia, and hydranencephaly with abnormal genitalia, which results in a fluid-filled sac replacing most of the brain tissue (hydranencephaly) and abnormal male genitalia.
For unknown reasons, the same mutation can result in the development of different conditions in different people, even among individuals within the same family. It is not clear why mutations in the ARX gene cause this array of conditions; researchers suggest that other genetic and environmental factors that have not been identified are likely involved.
Other Names for This Gene
- aristaless-related homeobox, X-linked
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
- Abedini SS, Kahrizi K, Behjati F, Banihashemi S, Ghasemi Firoozabadi S, Najmabadi H. Mutational screening of ARX gene in Iranian families with X-linked intellectual disability. Arch Iran Med. 2012 Jun;15(6):361-5. Citation on PubMed
- Bonneau D, Toutain A, Laquerriere A, Marret S, Saugier-Veber P, Barthez MA, Radi S, Biran-Mucignat V, Rodriguez D, Gelot A. X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (XLAG): clinical, magnetic resonance imaging, and neuropathological findings. Ann Neurol. 2002 Mar;51(3):340-9. doi: 10.1002/ana.10119. Citation on PubMed
- Cho IT, Lim Y, Golden JA, Cho G. Aristaless Related Homeobox (ARX) Interacts with beta-Catenin, BCL9, and P300 to Regulate Canonical Wnt Signaling. PLoS One. 2017 Jan 19;12(1):e0170282. doi: 10.1371/journal.pone.0170282. eCollection 2017. Citation on PubMed or Free article on PubMed Central
- Cossee M, Faivre L, Philippe C, Hichri H, de Saint-Martin A, Laugel V, Bahi-Buisson N, Lemaitre JF, Leheup B, Delobel B, Demeer B, Poirier K, Biancalana V, Pinoit JM, Julia S, Chelly J, Devys D, Mandel JL. ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia. Am J Med Genet A. 2011 Jan;155A(1):98-105. doi: 10.1002/ajmg.a.33785. Citation on PubMed
- Gecz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev. 2006 Jun;16(3):308-16. doi: 10.1016/j.gde.2006.04.003. Epub 2006 May 2. Citation on PubMed
- Guerrini R, Moro F, Kato M, Barkovich AJ, Shiihara T, McShane MA, Hurst J, Loi M, Tohyama J, Norci V, Hayasaka K, Kang UJ, Das S, Dobyns WB. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology. 2007 Jul 31;69(5):427-33. doi: 10.1212/01.wnl.0000266594.16202.c1. Citation on PubMed
- Itoh M, Takizawa Y, Hanai S, Okazaki S, Miyata R, Inoue T, Akashi T, Hayashi M, Goto Y. Partial loss of pancreas endocrine and exocrine cells of human ARX-null mutation: consideration of pancreas differentiation. Differentiation. 2010 Sep-Oct;80(2-3):118-22. doi: 10.1016/j.diff.2010.05.003. Epub 2010 Jun 9. Citation on PubMed
- Kato M, Dobyns WB. X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". J Child Neurol. 2005 Apr;20(4):392-7. doi: 10.1177/08830738050200042001. Citation on PubMed
- Lee K, Ireland K, Bleeze M, Shoubridge C. ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons. Neuroscience. 2017 Aug 15;357:220-231. doi: 10.1016/j.neuroscience.2017.06.010. Epub 2017 Jun 13. Citation on PubMed
- Marques I, Sa MJ, Soares G, Mota Mdo C, Pinheiro C, Aguiar L, Amado M, Soares C, Calado A, Dias P, Sousa AB, Fortuna AM, Santos R, Howell KB, Ryan MM, Leventer RJ, Sachdev R, Catford R, Friend K, Mattiske TR, Shoubridge C, Jorge P. Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. Mol Genet Genomic Med. 2015 May;3(3):203-14. doi: 10.1002/mgg3.133. Epub 2015 Feb 25. Citation on PubMed or Free article on PubMed Central
- Nasrallah IM, Minarcik JC, Golden JA. A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. J Cell Biol. 2004 Nov 8;167(3):411-6. doi: 10.1083/jcb.200408091. Citation on PubMed or Free article on PubMed Central
- Olivetti PR, Noebels JL. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Curr Opin Neurobiol. 2012 Oct;22(5):859-65. doi: 10.1016/j.conb.2012.04.006. Epub 2012 May 5. Citation on PubMed or Free article on PubMed Central
- Partington MW, Turner G, Boyle J, Gecz J. Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clin Genet. 2004 Jul;66(1):39-45. doi: 10.1111/j.0009-9163.2004.00268.x. Citation on PubMed
- Poirier K, Lacombe D, Gilbert-Dussardier B, Raynaud M, Desportes V, de Brouwer AP, Moraine C, Fryns JP, Ropers HH, Beldjord C, Chelly J, Bienvenu T. Screening of ARX in mental retardation families: Consequences for the strategy of molecular diagnosis. Neurogenetics. 2006 Mar;7(1):39-46. doi: 10.1007/s10048-005-0014-0. Epub 2005 Oct 19. Citation on PubMed
- Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr. 2003 Dec;15(6):567-71. doi: 10.1097/00008480-200312000-00004. Citation on PubMed
- Shoubridge C, Cloosterman D, Parkinson-Lawerence E, Brooks D, Gecz J. Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. Genomics. 2007 Jul;90(1):59-71. doi: 10.1016/j.ygeno.2007.03.005. Epub 2007 May 9. Citation on PubMed
- Shoubridge C, Fullston T, Gecz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat. 2010 Aug;31(8):889-900. doi: 10.1002/humu.21288. Citation on PubMed
- Shoubridge C, Tan MH, Seiboth G, Gecz J. ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. Hum Mol Genet. 2012 Apr 1;21(7):1639-47. doi: 10.1093/hmg/ddr601. Epub 2011 Dec 21. Citation on PubMed
- Stromme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lutcherath V, Gedeon AK, Wallace RH, Scheffer IE, Turner G, Partington M, Frints SG, Fryns JP, Sutherland GR, Mulley JC, Gecz J. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet. 2002 Apr;30(4):441-5. doi: 10.1038/ng862. Epub 2002 Mar 11. Citation on PubMed
- Suri M. The phenotypic spectrum of ARX mutations. Dev Med Child Neurol. 2005 Feb;47(2):133-7. doi: 10.1017/s001216220500023x. Citation on PubMed
- Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-Schafer H, Hehr U, Winkler J. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003 Jul 22;61(2):232-5. doi: 10.1212/01.wnl.0000079371.19562.ba. Citation on PubMed
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