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ARX
aristaless related homeobox
The ARX gene provides instructions for a protein essential in brain development, influencing the migration and communication of nerve cells and the formation of the pancreas, testes, and skeletal muscles. The ARX gene, or aristaless related homeobox, is a transcription factor vital for regulating other genes during embryonic development.
ARX is located on the short (p) arm of chromosome X, at band Xp21.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ARX gene (aristaless related homeobox) encodes a transcription factor that is crucial for embryonic development, particularly in the formation of various body structures. This protein is involved in the normal development of the brain, pancreas, testes, and skeletal muscles. Abnormalities in the ARX gene can lead to a range of neurological disorders and developmental conditions.
What the gene does
The ARX protein functions as a transcription factor, meaning it regulates the activity of other genes. It is part of the homeobox gene family, which plays a key role in early embryonic development. In the brain, the ARX protein is critical for the migration and communication of nerve cells (neurons), specifically directing interneurons to their correct locations. Beyond the brain, this protein also contributes to the differentiation of cells in the pancreas, testes, and skeletal muscles, ensuring they mature to perform their specialised roles. The homeobox domain of the ARX protein is responsible for its DNA binding capabilities, allowing it to interact with specific genetic sequences to regulate gene expression.
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Chromosome location
The ARX gene is situated on the X chromosome at position Xp21.3. This chromosomal location indicates that its inheritance pattern can differ between males and females, as males possess one X chromosome and females have two.
Protein structure
The ARX protein consists of 562 amino acids and contains several distinct regions. It has three disordered regions located at amino acids 1-21, 50-81, and 118-255. A critical Homeobox domain, responsible for DNA binding, is found between amino acids 328 and 387. Additionally, an OAR motif is present from amino acids 530 to 543.
Key variants
Variants in the ARX gene can lead to a diverse array of health conditions, primarily affecting neurological development. These genetic changes can range from small alterations to larger duplications or deletions within the gene. The specific type and location of an ARX variant often influence the severity and presentation of the associated condition.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1150C>T | p.Arg384Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 1 |
c.1223_1226dup | p.Leu410fs | Pathogenic | ★★☆☆ | X-linked lissencephaly with abnormal genitalia |
c.1471del | p.Pro490_Leu491insTer | Pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 1 |
c.1472del | p.Leu491fs | Pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 1 |
c.590del | p.Gly197fs | Pathogenic/Likely pathogenic | ★★☆☆ | X-linked ARX-related disorders |
c.880G>T | p.Glu294Ter | Pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 1 |
c.922G>T | p.Glu308Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.956C>A | p.Ser319Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ARX-related disorder |
c.994C>G | p.Arg332Gly | Pathogenic/Likely pathogenic | ★★☆☆ | Developmental and epileptic encephalopathy, 1 |
c.994C>T | p.Arg332Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Arachnoid cyst |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the ARX gene are linked to several inherited neurological disorders. These include developmental and epileptic encephalopathy 1, characterised by severe seizures and intellectual disability, and Partington syndrome, which presents with intellectual disability and movement difficulties affecting the hands. The gene is also associated with X-linked lissencephaly with abnormal genitalia (XLAG), a condition featuring abnormal brain development and genital anomalies. Furthermore, ARX variants can cause various forms of X-linked intellectual disability, sometimes without additional neurological problems.
UK clinical status
The ARX gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is listed as a 'green' gene on several PanelApp panels, including those for DDG2P, Differences in sex development, Dystonia, chorea or related movement disorder (childhood onset), Early onset dystonia, Early onset or syndromic epilepsy, Foetal anomalies, Intellectual disability, Intestinal failure or congenital diarrhoea, and Malformations of cortical development.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ARX gene?
The ARX gene provides instructions for creating a protein that acts as a transcription factor. This protein regulates other genes and is crucial for the proper development of the brain, particularly in the migration and communication of nerve cells, as well as the development of the pancreas, testes, and skeletal muscles.
What types of health conditions are associated with ARX gene variants?
Variants in the ARX gene are linked to a spectrum of neurological and developmental conditions. These include developmental and epileptic encephalopathy 1, Partington syndrome, X-linked lissencephaly with abnormal genitalia (XLAG), and various forms of X-linked intellectual disability.
Why is the ARX gene described as 'X-linked'?
The ARX gene is located on the X chromosome. This means that conditions caused by ARX variants often follow an X-linked inheritance pattern, which can result in different frequencies and severities of conditions in males versus females.
References
- Cho IT, Lim Y, Golden JA. Aristaless Related Homeobox (ARX) Interacts with β-Catenin, BCL9, and P300 to Regulate Canonical Wnt Signaling. PloS one. 2017. PMID: 28103279
- Lee K, Ireland K, Bleeze M. 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. PMID: 28627419
- Marques I, Sá MJ, Soares G. Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. Molecular genetics & genomic medicine. 2015. PMID: 26029707
- Shoubridge C, Tan MH, Seiboth G. ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. Human molecular genetics. 2012. PMID: 22194193
- Olivetti PR, Noebels JL. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Current opinion in neurobiology. 2012. PMID: 22565167
- Abedini SS, Kahrizi K, Behjati F. Mutational screening of ARX gene in Iranian families with X-linked intellectual disability. Archives of Iranian medicine. 2012. PMID: 22642246
- Cossée M, Faivre L, Philippe C. ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia. American journal of medical genetics. Part A. 2011. PMID: 21204215
- Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Human mutation. 2010. PMID: 20506206
- Itoh M, Takizawa Y, Hanai S. Partial loss of pancreas endocrine and exocrine cells of human ARX-null mutation: consideration of pancreas differentiation. Differentiation; research in biological diversity. 2010. PMID: 20538404
- Shoubridge C, Cloosterman D, Parkinson-Lawerence E. Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. Genomics. 2007. PMID: 17490853
- Guerrini R, Moro F, Kato M. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology. 2007. PMID: 17664401
- Poirier K, Lacombe D, Gilbert-Dussardier B. Screening of ARX in mental retardation families: Consequences for the strategy of molecular diagnosis. Neurogenetics. 2006. PMID: 16235064
- Gécz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Current opinion in genetics & development. 2006. PMID: 16650978
- Suri M. The phenotypic spectrum of ARX mutations. Developmental medicine and child neurology. 2005. PMID: 15707237
- Kato M, Dobyns WB. X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". Journal of child neurology. 2005. PMID: 15921244
- Partington MW, Turner G, Boyle J. Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clinical genetics. 2004. PMID: 15200506
- Nasrallah IM, Minarcik JC, Golden JA. A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. The Journal of cell biology. 2004. PMID: 15533998
- Uyanik G, Aigner L, Martin P. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003. PMID: 12874405
- Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Current opinion in pediatrics. 2003. PMID: 14631200
- Strømme P, Mangelsdorf ME, Shaw MA. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nature genetics. 2002. PMID: 11889467