Abstract
BackgroundCognitive 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.MethodsWe 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.ResultsMRX87 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.ConclusionOur 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.
Highlights
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
X-linked mental retardation (XLMR) is a heterogeneous genetic condition characterized by variable cognitive handicap with IQ below 70
The Aristaless related homeobox (ARX) protein contains a number of conserved domains, including the two DNA binding domains (Homeobox and Aristaless), and four distinct hydrophobic polyalanine tracts with a hypothetical role as transcriptional suppressor [17,18]
Summary
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. ARX encodes the Aristaless-related protein, a bi-functional homeobox transcription factor essential for cerebral patterning and for the maintenance of specific neuronal subtypes in the cerebral cortex [15] It belongs to the Q50 Paired-like (Prd-like) class genes, an ancient family of transcription factors with a key role in the early evolution of the animal head and development of the central nervous system [16]. The ARX protein contains a number of conserved domains, including the two DNA binding domains (Homeobox and Aristaless), and four distinct hydrophobic polyalanine tracts (polyA_I, II, III and IV) with a hypothetical role as transcriptional suppressor [17,18]
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