ARX mutation c.428–451dup (24bp) in a Brazilian family with X-linked mental retardation

Gestinari-Duarte, Raquel de Souza; Santos-Rebouças, Cíntia Barros; Boy, Raquel; Pimentel, Márcia Mattos Gonçalves

doi:10.1016/j.ejmg.2005.08.003

Cited by 9 publications

(8 citation statements)

References 15 publications

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“…As tract length increases over 20A in pA1 or pA2, a proportionate increase of mislocalized protein occurs. The 20A-pA2 mutation is at the 'tipping point' and subtle shifts in genetic or cellular environment might explain the clinical pleiotropy observed for this mutation (9,(11)(12)(13)(14)(15)(16).…”

Section: Cell-based Studies Of Pa Tract Expansion Mutationsmentioning

confidence: 99%

“…Greater than 97 families and isolated cases have been reported to carry one of the 44 ARX mutations (reviewed by (7,8)). The most frequent ARX mutation (∼39%; c.429_452dup(dup 24bp)) displays remarkable phenotypic pleiotropy (9,(11)(12)(13)(14)(15)(16). Recent studies identified ARX mutations in 9.5% of families with X-linked intellectual disability (XLID) (17) and in 7.5% of families with an obligate carrier female (18).…”

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confidence: 99%

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Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene

et al. 2011

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ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G>T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation.

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Section: Cell-based Studies Of Pa Tract Expansion Mutationsmentioning

confidence: 99%

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confidence: 99%

Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene

et al. 2011

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“…To date more than 50 XLMR genes have been recognized [1-3]. Each of them accounts for a very small proportion of the affected families with the exception of FMR1 , whose loss of function mutation causes the Fragile X syndrome, and the Aristaless X ( ARX ) gene mutated in several syndromic and non syndromic mentally retarded patients [4-9]. …”

Section: Introductionmentioning

confidence: 99%

“…The most frequent mutation is c.428_451dup24, also known as ARX dup24, a 24 bp duplication in exon 2 resulting in elongation of the second polyalanine tract (polyA 12 _II), that alone might account for 6.6% of all XLMR and 41% of families with mutations in ARX gene [4-9]. The c.428_451dup24 mutation has never been found in association with severe brain malformations (i.e.…”

Section: Introductionmentioning

confidence: 99%

MRX87 family with Aristaless Xdup24bp mutation and implication for polyAlanine expansions

et al. 2007

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Background: 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 intrafamilial heterogeneity, and provided insight into its molecular defect.

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“…This mutation was also observed in the proband's older brother, and in his cousin, both mentally retarded males. The family's clinical features have been previously detailed by us (Gestinari-Duarte et al 2006).…”

Section: Resultsmentioning

confidence: 99%

Mutational screening of ARX gene in Brazilian males with mental retardation of unknown etiology

2006

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ARX gene mutations have been known as important causes of developmental and neurological disorders and are responsible for a large spectrum of abnormal phenotypes, includeing syndromic as well as nonsyndromic forms of mental retardation. We have screened the entire coding and flanking intronic sequences of ARX gene in 143 mentally impaired males in order to investigate the contribution of ARX mutations to mental retardation in the population of Rio de Janeiro, Brazil. Three sequence variants were identified: one patient had the most recurrent mutation already observed in ARX gene, the c.428_451dup(24 bp), two patients presented the c.1347C>T (p.G449G) in exon 4, and one patient had the intronic variant c.1074-3T>C. Although two of these alterations were considered polymorphisms, the known pathogenic variant c.428_451dup(24 bp) was found at a high rate (4.8%) among X-linked mental retardation (XLMR) families. Our results, the first in Latin America, reinforce the idea that ARX mutations are relevant to mental retardation and are indicative that molecular screening of exon 2 should be considered in males with mental retardation of unknown etiology, associated or not with neurological manifestations, especially in familial cases.

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ARX mutation c.428–451dup (24bp) in a Brazilian family with X-linked mental retardation

Cited by 9 publications

References 15 publications

Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene

Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene

MRX87 family with Aristaless Xdup24bp mutation and implication for polyAlanine expansions

Mutational screening of ARX gene in Brazilian males with mental retardation of unknown etiology

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