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The novel Aristaless related homeobox gene, ARX, is widely expressed in the brain and is thought to play a key role in the regulation of brain development. Neurological phenotypes caused by ARX mutations have recently started to unfold. We describe a 72 year old man with X-linked mental retardation due to a 24 bp duplication mutation in exon 2 of t...
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... brain anomalies are not infrequently observed among mentally retarded individuals. In one population based study, structural brain anomalies were detected on neuroimaging in approximately 13% of individuals with prenatal aetiology behind mental retardation. 1 If the aetiology is genetic, it is likely that the brain anomalies are associated with the same underlying genetic mechanisms. We describe a man who was an affected member of a family with X-linked mental retardation. Linkage analysis mapped the disease gene to the distal part of the short arm on chromosome X. 2 The disease gene was subsequently identified to be the Aristaless related homeobox gene, ARX , localised in Xp22.1. 3 The ARX gene belongs to the paired class of homeobox genes. These genes are transcription factors important in the regulation of brain development. 4 Neurological features observed in the family in addition to mental retardation included infantile spasms, epilepsy, spasticity, and cerebellar ataxia. 2 All affected individuals were investigated with neuroimaging studies. Bilateral cerebral and cerebellar cavities resembling benign congenital cysts were demonstrated in one patient. The patient was a 72 year old man (fig 1) who lives in a home for the mentally handicapped. Little is known about his developmental milestones, although he has always been retarded and did not walk independently before the age of 5 years. He has only been hospitalised due to cholecystitis and pancreati- tis. There have been no episodes of acute neurological impairment or seizures. Due to behavioural abnormalities, he was treated with pimozide 15mg daily. Chorea-like movements in his arms and neck were subsequently recorded. The medi- cation was discontinued without any effect on the involuntary movements. On examination he had a broad based spastic ataxic gait with symmetric and generalised hyperreflexia, without plantar inversion. Skilled movements of the hands were impaired. Dystonia involving both hands and facial muscles was noted. Cognitive functioning was in the range for the mildly retarded (IQ 50–70). Blood pressure, pulse, total cholesterol, blood glucose, Doppler ultrasound examination of the precerebral arteries, and an electroencephalogram were normal. Molecular genetic studies of the ARX gene demonstrated a 428–451dup (24bp) mutation in exon 2. 3 The patho- genetic mechanism of this duplication, which results in addition of 8 extra alanine residues to the ARX protein, is currently not understood. MRI examination showed fluid filled cavities in both cerebral (fig 2A) and cerebellar hemispheres (fig 2B). The lesions were located to the outer surface of the brain tissue. The left cerebellar lesion appeared to be confined from the subarachnoidal space by a cavity wall. The signal intensities on T1, T2, and proton density images, showed that the cavity fluid was cerebrospinal fluid (CSF). Further evaluation with intrathecal contrast medium and CT was not performed. There was no retraction or displacement of the surrounding parenchyma. The total volume of both the frontal lobes and the cerebral hemispheres were approximately equal. The corpus callosum was hypoplastic in its caudal part, while the basal ganglia and brain stem appeared normal. MRI or CT of other affected individuals were either normal or demonstrated hypoplasia of the cerebellum and corpus callosum. 2 No other case with cavities was observed. Cerebral cystic lesions are unnatural cavities in which the continuity of the brain parenchyma is disrupted and replaced by fluid. Depending on the nature of the fluid content and the epithelial lining, cerebral cysts have been classified into the following categories: cysts containing CSF-like fluid, cysts with non-neural epithelium lining (colloid, epidermoid, and dermoid cysts), cysts associated with tumours, and infectious cysts. 5 The mucoid protein and lipids rich contents of non-neural epithelium lined cysts give rise to bright T1 weighted MRI signals, 6 not observed in the patient. Cysts associated with tumour or infection were unlikely considering lack of expansion and oedema in the surrounding tissues. Hence, the lesions in our patient were only compatible with the first category. This can be subdivided into three groups: ex vacuo type cysts (postraumatic leptomeningeal cysts, poren- cephalic cysts, or cysts resulting from surgical excision or vascular infarction), cysts with fluid secreting walls and CSF-like content (arachnoid and neuroepithelial cysts), and cysts associated with dysgenesis such as Dandy Walker and interhemi- spheric cysts. Porencephalic cysts frequently communicate with the ventricles and are associated with neurological defi- cits. Arachnoidal cysts are usually expansive and frequently located in the middle cranial fossa, while neuroepithelial cysts are formed within the ependymal lining of the ventricles. The dysgenesis group comprises heterogeneous developmental aetiologies, among which genetic aetiology should be considered. As the cavities were lying at the outer margins, infarcts due to small vessel disease could be considered as a cause. However, the largest lesion in the left frontal lobe was too extensive to represent small vessel occlusion. Other features not favouring a vascular aetiology were lack of retraction in the surrounding parenchyma, and localisation of the lesions outside the watershed areas. Also, there was no history of acute neurological impairment, and he had no identifiable risk factors for cerebrovascular disease. Generalised hyperreflexia and cerebellar ataxia belonged to the phenotype associated with the mutation. However, the patient was not more spastic, ataxic, or mentally retarded than other affected individuals in the family. The lesions had therefore probably not contributed significantly to his motor or intellectual disabilities. The fact that he learned to walk independently at the age of 5 years suggested that the cause of his motor problems was congenital. Dystonia has also been observed in several other families affected by the same duplication mutation of the ARX gene. This particular mutation is associated with a wide range of neurological phenotypes. 7 8 The most likely explanation for the cystic cavities was abnormalities of the developing foetal brain caused by the ARX mutation. The gene is widely expressed in the brain, including the telencephalon, ventral thalamus, cerebral cortex, amyg- dala, corpus callosum, caudate nucleus, and hippocampus. 9 In a knock out mouse model Arx was recently shown to play an important role in neuronal proliferation and interneuronal migration and differentiation, as well as testicular differentiation. In humans, some ARX mutations were also shown to cause X-linked lissencephaly with ambiguous genitalia (XLAG). 10 Mutations in the paired class of homeobox genes have been associated with malformations in the central nervous system, including the ocular region. 11 Unilateral microph- thalmia and structural brain asymmetry occurred in a boy with infantile spasms who had a deletion mutation of exon 5 of the ARX gene. 3 The frequency of congenital cysts associated with mutations may not be high, although several affected individuals have not yet been studied with MRI. Interestingly, a large posterior fossa cyst was reported in one other case with an ARX mutation, a missense mutation of exon 2 associated with myoclonic epilepsy. 12 Abnormalities in organs outside the central nervous system and genitourinary tract have not been reported. In conclusion, it was most likely that the cystic cavities were related to the mutation in the ARX homeobox gene. The spec- trum of phenotypes caused by mutations in this gene will probably expand as more cases become diagnosed. This work was supported by The Unger-Vetlesen Medical Fund, Jersey, The Research Council of Norway and The National Health and Medical Research Council of Australia. We thank Rolf Nyberg-Hansen, Department of Neurology and Bengt Frode Kase, Department of Pae- diatric Research, Rikshospitalet, The National Hospital, Oslo, Norway, for review of the ...
Citations
... | 7 (RUNX) , holoprosencephaly (ZIC2) (Brown et al., 1998), hand-foot-genital syndrome (HOXA13) (Goodman et al., 2000), ovarian failure (FOXL2; autosomal dominant) (Harris et al., 2002), congenital central hypoventilation syndrome (PHOX2B; ASCL1) (Amiel et al., 2003), X-linked intellectual disability (ARX) (Stromme et al., 2003), blepharophimosis, ptosis, and epicanthus inversus (FOXL2; autosomal recessive) (Nallathambi et al., 2007), and X-linked heterotaxy (ZIC3) (Wessels et al., 2010). ...
Synpolydactyly 1 (SPD; MIM# 186000), also called syndactyly type II (SDTY2), is a genetic limb malformation characterized by polydactyly with syndactyly involving the webbing of the third and fourth fingers, and the fourth and fifth toes. It is caused by heterozygous alterations in HOXD13 with incomplete penetrance and phenotypic variability. In our study, a five-generation family with an SPD phenotype was enrolled in our Rare Disease Genomics Protocol. A comprehensive examination of three generations using Illumina short-read whole-genome sequencing (WGS) did not identify any causative variants. Subsequent WGS using Pacific Biosciences (PacBio) long-read HiFi Circular Consensus Sequencing (CCS) revealed a heterozygous 27-bp duplication in the polyalanine tract of HOXD13. Sanger sequencing of all available family members confirmed that the variant segregates with affected individuals. Re-analysis of an unrelated family with a similar SPD phenotype uncovered a 21-bp (7-alanine) duplication in the same region of HOXD13. Although ExpansionHunter identified these events in most individuals in a retrospective analysis, low sequence coverage due to high GC content in the HOXD13 polyalanine tract makes detection of these events challenging. Our findings highlight the value of long-read WGS in elucidating the molecular etiology of congenital limb malformation disorders.
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... Kitamura et al. were the first to confirm that truncating or missense mutations of the ARX gene are linked to an XLAG phenotype in mice (22). These studies were followed up by screening for, and confirmation of, 'loss-of-function' ARX mutations in families with XLAG phenotypes (23,24). By contrast, other less severe ARX-related disorders were shown to be generally associated with hypomorphic and expansion mutations. ...
... Again, besides being related to the poly-Ala expansion-driven X-linked mental retardation [258], mutations ARX are related to agenesis of the corpus callosum in females and X-linked lissencephaly with abnormal genitalia in males [259], early infantile epileptic encephalopathy-1 [260,261], Partington syndrome [261], and X-linked lissencephaly-2 [259,262]. It was also pointed out that duplication mutation of ARX can cause benign bilateral cystic-like cavities in the cerebral and cerebellar hemispheres [263]. Figure 2H and Figure S1H show that human forkhead box protein L2 (FOXL2, UniProt ID: P58012) is predicted to have very high levels of intrinsic disorder, possessing the MobiDB consensus disorder score of 47.34%. ...
Intrinsically disordered proteins and proteins with intrinsically disordered regions have been shown to be highly prevalent in disease. Furthermore, disease-causing expansions of the regions containing tandem amino acid repeats often push repetitive proteins towards formation of irreversible aggregates. In fact, in disease-relevant proteins, the increased repeat length often positively correlates with the increased aggregation efficiency and the increased disease severity and penetrance, being negatively correlated with the age of disease onset. The major categories of repeat extensions involved in disease include poly-glutamine and poly-alanine homorepeats, which are often times located in the intrinsically disordered regions, as well as repeats in non-coding regions of genes typically encoding proteins with ordered structures. Repeats in such non-coding regions of genes can be expressed at the mRNA level. Although they can affect the expression levels of encoded proteins, they are not translated as parts of an affected protein and have no effect on its structure. However, in some cases, the repetitive mRNAs can be translated in a non-canonical manner, generating highly repetitive peptides of different length and amino acid composition. The repeat extension-caused aggregation of a repetitive protein may represent a pivotal step for its transformation into a proteotoxic entity that can lead to pathology. The goals of this article are to systematically analyze molecular mechanisms of the proteinopathies caused by the poly-glutamine and poly-alanine homorepeat expansion, as well as by the polypeptides generated as a result of the microsatellite expansions in non-coding gene regions and to examine the related proteins. We also present results of the analysis of the prevalence and functional roles of intrinsic disorder in proteins associated with pathological repeat expansions.
... This is further supported by recent investigations into interneuron development, with both mutant models demonstrating a similar reduction in calbindin positive interneurons within the newborn cortex (K. Lee, 192 Stromme et al., 2002a192 Stromme et al., , 2002bKato et al., 2003;Cossee et al., 2011;Mirzaa et al., 2013;Michaud et al., 2014PRT 11/55 39/192 Bienvenu et al., 2002Stromme et al., 2002aStromme et al., , 2002bPartington et al., 2004;Poirier et al., 2006;Rujirabanjerd et al., 2007;Cossee et al., 2011;Gronskov et al., 2014;Marques et al., 2015NS-XLID 37/55 137/192 Bienvenu et al., 2002Stromme et al., 2002aStromme et al., , 2002bStromme et al., 2003;Partington et al., 2004;Van Esch et al., 2004;Poirier et al., 2005;Stepp et al., 2005;Gestinari-Duarte Rde et al., 2006;Nawara et al., 2006;Poirier et al., 2006;Szczaluba et al., 2006;Laperuta et al., 2007;Rujirabanjerd et al., 2007;Abedini et submitted Neurobiology), the same interneuron subtype that responded to 17β-estradiol administration in PA1 hemizygous mice (Olivetti et al., 2014). In line with the increase in deregulated genes harbouring an estrogen response element (Mattiske et al., 2016), and the known involvement of Arx/ARX in pancreatic development and maintenance (Collombat et al., 2003;Du et al., 2012), it was not surprising to find that disease manifestation clustered around key periods of hormonal and nutritional change. ...
... Not reported in this study c.430_456dup(27 bp) Stromme et al. (2003) ...
The Aristaless-related homeobox (ARX) gene is implicated in intellectual disability with the most frequent pathogenic mutations leading to expansions of the first two polyalanine tracts. Here, we describe analysis of the ARX gene outlining the approaches in the Australian and Portuguese setting, using an integrated clinical and molecular strategy. We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non-pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX-related disorders is crucial for an adequate clinical follow-up and accurate genetic counseling of at-risk family members.
... The Rhox cousins, Arx and Esx1, are also expressed in cancerous cells. Mutation of ARX is linked to the formation of brain cysts (59), but few if any of the ~400 papers detailing Arx/ARX expression and function in developmental processes mention aberrant expression in tumor cell lines. Conversely, Esx1 was detected by northern blot in ~40% of mouse tumor lines (37), and is a significant player in human colorectal carcinomas (60). ...
Homeobox genes encode transcription factors that have well-established roles in embryonic development. We recently discovered the Rhox genes, a new family of homeobox genes, which are selectively expressed in the developing embryo, postnatal and adult gonads, and accessory tissues associated with mammalian reproduction. The largest and best-characterized Rhox cluster is found in mouse. However, all mammals examined to date possess a set of Rhox genes that, while they may vary in number by species, appear relevant to reproduction and are located in the syntenic region of the X chromosome. Rhox5, the founding member of the family, was initially cloned from a screen to identify tumorigenic antigens from T-cell lymphomas, and was later found to be widely expressed in tumors from tissues of diverse origins that do not normally express the Rhox genes. This aberrant upregulation appears to be a general feature of many Rhox genes, but the implications of this misexpression remain largely uninvestigated. In this review, we will discuss the latest findings on the normal and abnormal roles of the Rhox genes and their potential contributions to the formation and progression of tumors.
... At the bottom of the figure: ARX protein functional domains and polyA tracts are shown, next to the various mutations that results in a spectrum of developmental brain phenotypes. *[10], #[13], °[14], ^[19], §[27], ∑[30], ≠[31], $[32], &[33] . ble expression. ...
... The ARXdup24 underlies only a part of the complex phenotypic spectrum of ARX mutations. We can distinguish three groups of ARX mutations with different outcomes (Figure 3)101112131419,27,30313233 : 1. severe mutations causing severe brain patterning malformations due to alterations of the DNA binding domains (HD and Aristaless); 2. expansion in the polyA_I motif causing familial ISSX phenotypes ; 3. expansion in the polyA_II motif (c.428_451dup24) causing a spectrum of XLMR conditions with huge inter-and intra-familial heterogeneity. With the exception of the severe ARX alterations classified as "loss of function", we cannot establish the functional effect of the polyA expansion mutations. ...
Cognitive impairments are heterogeneous conditions, and it is estimated that 10% may be caused by a defect of mental function genes on the X chromosome. One of those genes is Aristaless related homeobox (ARX) encoding a polyA-rich homeobox transcription factor essential for cerebral patterning and its mutations cause different neurologic disorders. We reported on the clinical and genetic analysis of an Italian family with X-linked mental retardation (XLMR) and intra-familial heterogeneity, and provided insight into its molecular defect.
We carried out on linkage-candidate gene studies in a new MRX family (MRX87). All coding regions and exon-intron boundaries of ARX gene were analysed by direct sequencing.
MRX87 patients had moderate to profound cognition impairment and a combination of minor congenital anomalies. The disease locus, MRX87, was mapped between DXS7104 and DXS1214, placing it in Xp22-p21 interval, a hot spot region for mental handicap. An in frame duplication of 24 bp (ARXdup24) in the second polyAlanine tract (polyA_II) in ARX was identified.
Our study underlines the role of ARXdup24 as a critical mutational site causing mental retardation linked to Xp22. Phenotypic heterogeneity of MRX87 patients represents a new observation relevant to the functional consequences of polyAlanine expansions enriching the puzzling complexity of ARXdup24-linked diseases.
... Congenital frontal cavities have been reported in individuals with the ARX c.428_451dup24. 9 The phenomenon of testis enlargement was found in only one family (Family 1). Adults in this pedigree had testis volumes of 25 to 30 mL. ...
We screened 165 mentally retarded patients for ARX gene 428-451 base pair (bp) duplication. Eighteen individuals from five families were found to carry the duplication, and all had intellectual impairment. Twelve presented with focal hand dystonia, while six patients had EEG abnormalities including seizures. Other symptoms included speech difficulties (4/18), testis enlargement (4/18), lower limb spasticity or foot dystonia (4/18), and facial telangiectasia (3/18). These features confirm the pleiotropic effect of the duplication.
... Three of the four polyalanine tracts are encoded in exon 2, and the first and second polyalanine tracts are mutation hot spots causing mental retardation and epilepsy including West syndrome (Bienvenu et al., 2002; Stromme et al., 2002a Stromme et al., , 2002b). To date, 101 patients from 20 families and 3 sporadic patients with the 24 base-pair expansion in the second polyalanine tract have been reported (Bienvenu et al., 2002; Stromme et al., 2002a Stromme et al., , 2003 Gronskov et al., 2004; Partington et al., 2004; Van Esch et al., 2004; Poirier et al., 2005; Stepp et al., 2005). The 24 base-pair duplication in the second polyalanine tract exhibits pleiotropic effects, such as familial or sporadic West syndrome, dystonia or Partington syndrome, autism, and non-syndromic mental retardation , brain cysts, and transsphenoidal encephalocele. ...
Symptomatic West syndrome has heterogeneous backgrounds. Recently, two novel genes, ARX and CDKL5, have been found to be responsible for cryptogenic West syndrome or infantile spasms. Both are located in the human chromosome Xp22 region and are mainly expressed and play roles in fetal brain. Moreover, several genes responsible for brain malformations including lissencephaly, which is frequently associated with West syndrome or infantile spasms, have been found, and the mechanisms responsible for the neural network disorders in these brain malformations are rapidly being determined. Findings of animal and in vitro studies and mutation analyses in humans are delineating the molecular and cellular basis of West syndrome.
... An adult male from the family with XLMR and infantile spasms reported by Strømme et al. had benign developmental cysts in the cerebral and cerebellar hemispheres. 27,37 In another family which included four males with mental retardation, one of the affected males was born with a median cleft lip and palate, agenesis of the corpus callosum, and a frontobasal transsphenoidal encephalocele extending into the epipharynx; he developed partial anterior hypopituitarism in early infancy. 38 His brother had moderate mental retardation and macrocephaly. ...
Mutations in the ARX gene can result in many different phenotypes, including phenotypes associated with severe brain malformations and less severe phenotypes associated with syndromic or non-syndromic forms of XLMR. There seems to be a consistent genotype-phenotype correlation and both interfamilial and intrafamilial variability of expression of some of the mutations, particularly the common 428-451dup(24 bp) mutation. Familiarity with the phenotypic spectrum of ARX mutations is helpful in determining when to request ARX mutation analysis.
