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Intellectual disability is the most common
neurodevelopmental defect in the world. This disorder affects 1-3% of the
general population. X-linked intellectual disability (XLID) is the frequent
form of intellectual disability which includes a heterogeneous group of
inherited disorders emerging as various degrees of intellectual disabilities.
Phenotypically, XLID is subdivided into syndromic (S-XLID) and non-syndromic
(NS-XLID) forms; where two-thirds of the XLID cases are thought to be
non-syndromic. Among the non-syndromic form, the aristaless-related homeobox
gene (ARX) is one of the ideal candidates to be evaluated in NS-XLID, since its
mutations are responsible for about 9.5% of XLID cases. Based on the previous
literature, mutations in the ARX gene influence the critical processes
associated with brain development. Our bioinformatics results showed that the
ARX is a highly conserved protein with a substantial role in an important
developmental pathway; and its deficiency can cause irreversible defects, mainly
in the brain, that leads to the development of XLID. Moreover, we addressed the
structural properties of the ARX protein to decipher the important role of the
ARX gene in the integrity of normal brain development.
Keywords: ARX, X-linked intellectual disability, Protein structure,
Wnt/β-catenin signaling
INTRODUCTION
Intellectual disability (ID) is the most
frequent neurodevelopmental disorder in the world characterized by an
intelligence quotient (IQ) below 70 [1]. The prevalence of ID is approximately
2-3% in the general population [2-8]. ID or associated phenotypes resulted from
a monogenic defect are subdivided into 4 categories according to the mode of
inheritance, autosomal dominant ID, autosomal recessive ID, X-linked ID and
mitochondrial ID [9-13]. Mutations in X-linked genes account for 5-10% of all
types of ID and are the most likely causes of ID in males [14].
ARX GENE: STRUCTURE
AND FUNCTION
The Aristaless-related homeobox gene (ARX) is
located on the Xp22.13. It consists of 5 exons (Figure 1) and is transcribed into 2.8 kb mRNA. The structure of
the ARX protein consists of several different compartments, including [15-18]:
1) A highly conserved homeobox domain (repressor domain) that spans the amino
acids from 328 to 387. This domain directly binds to DNA [19]; 2) C-terminal
OAR or aristaless domain (activator domain) which spans the amino acids from
530 to 543 of protein (Figure 1)
[20]; 3) Octapeptid domain which is a receptor site beside the N-terminal of
the ARX protein for some enhancer proteins that contribute to ARX functional
activity adjustments [21]; 4) Four polyalanine tracts which are located between
Hundredth-degree amino acids and 115, 144 and155, 278 and281, also 432 and 440,
that each one has 16, 12, 7 and 9 residues, respectively [22-24]. It was determined that the ARX
gene is evolutionarily conserved in different species and according to Figure 2; it has a high local
similarity to its target binding sites. Also, the sequence alignment of this
protein with other species (Figure 3)
confirms that the functional domains of ARX protein are highly conserved, thus
it has been predicted that the mutations of this gene can be highly pathogenic
[25-35].
ARX AND THE FREQUENCY OF ITS
MUTATIONS
According to European XLID consortium, mutations of
ARX gene has been found in 9.5% of families with X-linked intellectual
disability and 7.5% of large families with 2 or more affected males from
multi-generations that are related with each other through an obligate carrier
female [21,36-38].
ARX-ASSOCIATED
PHENOTYPES
ARX incapacitate mutations
through exons and introns and subsequently different domains, are associated
with a wide spectrum of phenotypes ranging from severe developmental
abnormalities of the brain to syndromic forms of XLID. Early infantile
epileptic encephalopathy-type1 (OMIM#308350); Lissencephaly-type2
(OMIM#300215); Hydranencephaly with abnormal genitalia (OMIM#300215); Proud
Syndrome (OMIM#300004); Partington Syndrome (OMIM# 309510); X-linked Mental
retardation and ARX-related (OMIM#300419) are the known various syndromic
phenotypes associated with ARX mutations [39-43]. Nonetheless, how different
mutations in this single transcription factor can produce different phenotypes
is not completely understood.
During the recent theory of
Il-Taeg Cho et al. [44], the ARX gene has interaction with different
cofactors/transcription factors and regulates single target genes in different
cell types. According to Il-Taeg Cho’s study, by using the proteomics method,
it was determined that the Wnt/β-catenin signaling pathway includes three
components such as B-cell CLL/lymphoma 9 (BCL9), β-catenin (CTNNB1) and
leucine-rich repeat flightless interacting protein 2 (LRRFIP2). They showed
that ARX positively controls Wnt/β-catenin signaling and that the C-terminal
domain of ARX interacts with the armadillo repeats of β-catenin to move forward
Wnt/β-catenin signaling.
Furthermore, they understood that P300 and
BCL9 also interact with ARX to adjust Wnt/β-catenin signaling. These data offer
new insights into how ARX can exclusively regulate cortical neurogenesis and
link the role of ARX with Wnt/β-catenin signaling [44] (Figure 4).
BIOINFORMATICS
ANALYSIS
To study the molecular features,
the structure of the ARX gene, bioinformatics analysis was performed using the
ExPASy tool and SWISS-MODEL server, respectively. The phylogeny tree of ARX
protein was also drawn using the software.
As illustrated in Figure 3, it was determined that the
ARX gene is evolutionarily conserved in different species. Moreover, the
sequence alignment of this protein with other spices confirms that the
functional domains of ARX protein are highly conserved, and therefore it has
been predicted that the mutations of this gene can be highly pathogenic.
WEB
RESOURCES
The
URLs for data offered here are as follows:
NCBI database (http://www.ncbi.nlm.nih.gov)
SWISS-MODEL
server (http://swissmodel.expasy.org)
Phylogeny software (http://phylogeny.lirmm.fr)
Expasy
software (http://www.expasy.org/)
Ensembl Genome Browser (http://www.ensembl.org)
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