Reviewed August 2013
What is the official name of the ARX gene?
The official name of this gene is “aristaless related homeobox.”
ARX is the gene's official symbol. The ARX gene is also known by other names, listed below.
What is the normal function of the ARX gene?
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 pancreas, testes, brain, 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.
Does the ARX gene share characteristics with other genes?
The ARX gene belongs to a family of genes called homeobox (homeoboxes).
A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.
How are changes in the ARX gene related to health conditions?
- Partington syndrome - caused by mutations in the ARX gene
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 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 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. This type of mutation is called a polyalanine repeat expansion. The expansion likely impairs ARX protein function and may disrupt normal interneuron migration in the developing brain, leading to the intellectual disability and dystonia characteristic of Partington syndrome.
- X-linked infantile spasm syndrome - caused by mutations in the ARX gene
Mutations in the ARX gene can cause X-linked infantile spasm syndrome, 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 most common ARX gene mutations that cause X-linked infantile spasm syndrome are polyalanine repeat expansions that add extra alanines to the first or second polyalanine tract in the ARX protein. How these expansions lead to X-linked infantile spasms is unknown. Other ARX gene mutations that cause this condition are believed to reduce the function of the ARX protein. However, it is unclear how a decrease in ARX protein function leads to seizures and intellectual disability.
- X-linked lissencephaly with abnormal genitalia - caused by mutations in the ARX gene
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.
- other disorders - caused by mutations in the ARX gene
Different 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 X-linked intellectual disability. XLID can occur in combination with other neurological problems as part of distinct conditions called X-linked intellectual disability syndromes. ARX gene mutations account for 9.5 percent of all cases of XLID.
ARX gene mutations cause several X-linked intellectual disability syndromes, including X-linked lissencephaly with abnormal genitalia, X-linked infantile spasm syndrome, 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.
Where is the ARX gene located?
Cytogenetic Location: Xp21.3
Molecular Location on the X chromosome: base pairs 25,003,693 to 25,015,947
The ARX gene is located on the short (p) arm of the X chromosome at position 21.3.
More precisely, the ARX gene is located from base pair 25,003,693 to base pair 25,015,947 on the X chromosome.
See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.
Where can I find additional information about ARX?
You and your healthcare professional may find the following resources about ARX helpful.
Educational resources - Information pages
- Neuroscience (second edition, 2001): Early Brain Development (http://www.ncbi.nlm.nih.gov/books/NBK11113/)
- Neuroscience (second edition, 2001): Neuronal Migration (http://www.ncbi.nlm.nih.gov/books/NBK10831/)
Genetic Testing Registry - Repository of genetic test information
- GTR: Genetic tests for ARX (http://www.ncbi.nlm.nih.gov/gtr/tests/?term=170302%5Bgeneid%5D)
You may also be interested in these resources, which are designed for genetics professionals and researchers.
- PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=%28%28ARX%5BTIAB%5D%29%20OR%20%28aristaless%20related%20homeobox%5BTIAB%5D%29%29%20AND%20%28%28Genes%5BMH%5D%29%20OR%20%28Genetic%20Phenomena%5BMH%5D%29%29%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%201440%20days%22%5Bdp%5D)
OMIM - Genetic disorder catalog
- ARISTALESS-RELATED HOMEOBOX, X-LINKED (http://omim.org/entry/300382)
- CORPUS CALLOSUM, AGENESIS OF, WITH ABNORMAL GENITALIA (http://omim.org/entry/300004)
- EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 1 (http://omim.org/entry/308350)
- MENTAL RETARDATION, X-LINKED, WITH OR WITHOUT SEIZURES, ARX-RELATED (http://omim.org/entry/300419)
Research Resources - Tools for researchers
- Atlas of Genetics and Cytogenetics in Oncology and Haematology (http://atlasgeneticsoncology.org/Genes/GC_ARX.html)
- HGNC Gene Family: Homeoboxes / PRD class (http://www.genenames.org/genefamilies/homeobox)
- HGNC Gene Symbol Report (http://www.genenames.org/cgi-bin/gene_symbol_report?q=data/hgnc_data.php&hgnc_id=18060)
- NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/170302)
What other names do people use for the ARX gene or gene products?
- aristaless-related homeobox, X-linked
See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.
What glossary definitions help with understanding ARX?
amino acid ;
corpus callosum ;
mental retardation ;
You may find definitions for these and many other terms in the Genetics Home Reference
- 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. doi: 012156/AIM.009. (http://www.ncbi.nlm.nih.gov/pubmed/22642246?dopt=Abstract)
- OMIM: ARISTALESS-RELATED HOMEOBOX, X-LINKED (http://omim.org/entry/300382)
- Bonneau D, Toutain A, Laquerrière A, Marret S, Saugier-Veber P, Barthez MA, Radi S, Biran-Mucignat V, Rodriguez D, Gélot 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. (http://www.ncbi.nlm.nih.gov/pubmed/11891829?dopt=Abstract)
- Cossée 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. (http://www.ncbi.nlm.nih.gov/pubmed/21204215?dopt=Abstract)
- Forman MS, Squier W, Dobyns WB, Golden JA. Genotypically defined lissencephalies show distinct pathologies. J Neuropathol Exp Neurol. 2005 Oct;64(10):847-57. (http://www.ncbi.nlm.nih.gov/pubmed/16215456?dopt=Abstract)
- Gécz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Curr Opin Genet Dev. 2006 Jun;16(3):308-16. Epub 2006 May 2. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16650978?dopt=Abstract)
- 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. (http://www.ncbi.nlm.nih.gov/pubmed/17664401?dopt=Abstract)
- 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. (http://www.ncbi.nlm.nih.gov/pubmed/20538404?dopt=Abstract)
- 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. (http://www.ncbi.nlm.nih.gov/pubmed/15921244?dopt=Abstract)
- 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. (http://www.ncbi.nlm.nih.gov/pubmed/15533998?dopt=Abstract)
- NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/170302)
- 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. Review. (http://www.ncbi.nlm.nih.gov/pubmed/22565167?dopt=Abstract)
- Partington MW, Turner G, Boyle J, Gécz 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. (http://www.ncbi.nlm.nih.gov/pubmed/15200506?dopt=Abstract)
- 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. Epub 2005 Oct 19. (http://www.ncbi.nlm.nih.gov/pubmed/16235064?dopt=Abstract)
- 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. Review. (http://www.ncbi.nlm.nih.gov/pubmed/14631200?dopt=Abstract)
- Shoubridge C, Cloosterman D, Parkinson-Lawerence E, Brooks D, Gécz J. Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. Genomics. 2007 Jul;90(1):59-71. Epub 2007 May 9. (http://www.ncbi.nlm.nih.gov/pubmed/17490853?dopt=Abstract)
- Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat. 2010 Aug;31(8):889-900. doi: 10.1002/humu.21288. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20506206?dopt=Abstract)
- Shoubridge C, Gardner A, Schwartz CE, Hackett A, Field M, Gecz J. Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation? Eur J Hum Genet. 2012 Dec;20(12):1311-4. doi: 10.1038/ejhg.2012.61. Epub 2012 Apr 11. (http://www.ncbi.nlm.nih.gov/pubmed/22490986?dopt=Abstract)
- Shoubridge C, Tan MH, Seiboth G, Gécz 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. (http://www.ncbi.nlm.nih.gov/pubmed/22194193?dopt=Abstract)
- Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, Lütcherath V, Gedeon AK, Wallace RH, Scheffer IE, Turner G, Partington M, Frints SG, Fryns JP, Sutherland GR, Mulley JC, Gécz J. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat Genet. 2002 Apr;30(4):441-5. Epub 2002 Mar 11. (http://www.ncbi.nlm.nih.gov/pubmed/11889467?dopt=Abstract)
- Suri M. The phenotypic spectrum of ARX mutations. Dev Med Child Neurol. 2005 Feb;47(2):133-7. Review. (http://www.ncbi.nlm.nih.gov/pubmed/15707237?dopt=Abstract)
- Turner G, Partington M, Kerr B, Mangelsdorf M, Gecz J. Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. Am J Med Genet. 2002 Nov 1;112(4):405-11. (http://www.ncbi.nlm.nih.gov/pubmed/12376946?dopt=Abstract)
- Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Marschner-Schäfer H, Hehr U, Winkler J. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003 Jul 22;61(2):232-5. (http://www.ncbi.nlm.nih.gov/pubmed/12874405?dopt=Abstract)
The resources on this site should not be used as a substitute for
professional medical care or advice. Users seeking information about
a personal genetic disease, syndrome, or condition should consult with a qualified
See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.