ARX: a gene for all seasons
Introduction
The Aristaless-related homeobox gene, ARX, belongs to a large family of homeodomain transcription factors with crucial roles in development [1]. Initially, the Arx gene was isolated and characterised in zebrafish and mice [2], on the basis of its similarity to the Drosophila gene aristaless. The discovery of the human ortholog followed in 2002, when the ARX gene mutations were identified in patients with X-linked West syndrome (otherwise known as X-linked infantile spasms syndrome [3]) Partington syndrome [3], X-linked lissencephaly with ambiguous genitalia [4], X-linked myoclonic epilepsy with generalized spasticity and intellectual disability [3], and non-syndromic X-linked mental retardation [3, 5]. To date, more than 60 different families and isolated cases have been reported to carry an ARX mutation. Although a general picture of genotype–phenotype correlation is emerging, the striking pleiotropy of ARX mutations is still poorly understood and puzzling [6••].
In this review, we summarize currently known ARX mutations and their phenotypic consequences. We focus primarily on those implicated in non-syndromic X-linked mental retardation. Among these, we discuss in particular the duplication of 24 bp (c.428-451dup) that leads to an expansion of one of the ARX protein polyalanine tracts, from 12 to 20 alanines. To date, this is the most prevalent ARX mutation, occurring in more than 40% of all unrelated patients with ARX mutations.
Section snippets
The ARX gene
The ARX gene is located at Xp22 near to the POLA gene. It is a relatively small gene of ∼12.5 kb and has five coding exons. In addition to a ∼2.8 kb transcript identified in the brain and skeletal muscle [3], northern blot analysis indicated the existence of larger isoforms in heart (∼4.4 kb, [5]; ∼5.9 kb, [7]) and shorter isoforms (∼2.5 kb and ∼2.1 kb) in skeletal muscle [3]. However, the structure of the ARX gene, available expressed sequence tags, and the analysis of its orthologs all suggest that
ARX mutations
Since the discovery of the ARX gene in 2002, several groups have screened the gene in patient cohorts of varying size and composition. Some of these results were summarized by Kato et al. [6••], Mandel and Chelly [11], and Poirier et al. [12••]. For the purpose of this review, we capture and discuss the information on 59 ARX gene mutations reported since 2002 (Table 1). These 59 cases represent 32 different mutations, including 2 splice site mutations, 3 nonsense mutations, 12 missence
Genotype–phenotype
There are about seven different conditions, with or without malformations, in which ARX gene mutations have been identified to date. These are summarized in Table 2 in the order of their severity in terms of patient phenotype. The emerging genotype–phenotype correlation has been discussed in more detail by others [6••, 20, 21]. In general, truncation mutations and missense mutations in crucial, evolutionarily conserved residues lead to more severe outcomes, whereas the polyalanine expansion
ARX-screening and the contribution of ARX mutations to mental retardation
The ARX gene is one of the estimated ∼100 genes involved in X-linked mental retardation [24]. Although its contribution is not yet precisely established, ARX is emerging as one of the more important genes [25•]. On the basis of their data, Partington et al. [13] speculated that the population frequency of the most frequent ARX mutation, the c.428_451dup mutation, is likely to be 1 in 12 000 males, which is about one third of that for fragile X mutations (1 in 4000 [26]). Considering that the
Molecular pathology
The wide spectrum of phenotypes associated with ARX mutations is a reflection of the complexity associated with the structure and function of the ARX protein structure and function. The ARX protein has many important functional domains, which include the paired/Q50 homeodomain (aa 328–387), the Aristaless (aa 527–542), octapeptide (aa 27–34) and acidic (aa 224-255) domains, four polyalanine tracts (Ala1, aa 100–115; Ala2, aa 144–155; Ala3, aa 275–281; and Ala4, aa 432–440), and three nuclear
Conclusions
Mental retardation is a highly heterogeneous condition with a variety of contributing factors, both genetic and environmental. The ARX gene is emerging as an important factor that might even rival fragile X. Unlike most other single gene disorders, ARX mutations show striking pleiotropy and often puzzling intra- and inter-familial variation. However, with the growing number of ARX mutations identified, a more solid picture of genotype–phenotype correlation is surfacing. This will greatly assist
Update
Friocourt et al. [40•] recently reviewed the role of the ARX protein in cortical development. The role of Arx in regional localisation, tangential and radial neuronal migration, and cell proliferation and differentiation was discussed. By contrast, Nawara et al. [41••] screened a set of 165 probands who had confirmed or suggestive X-linked mental retardation and who were negative for FRAXA mutation. They found five novel c.428_451dup mutations. Their results further confirm the high prevalence
Electronic database information and accession numbers
The Online Mendelian Inheritance in Man (OMIM) database was accessed at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM; ARX gene and protein information was accessed at Entrez Gene http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene; (ARX gene, MIM no. 300382, GenBank no. NM_139058). Homeobox resource pages: http://research.nhgri.nih.gov/homeodomain/.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors would like to thank GR Sutherland for his constructive comments to the manuscript. This work was carried out with the support of the National Health and Medical Research Council of Australia.
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