ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation

InvestigationofacriticalregionforanX-linkedmentalretardation(XLMR)locusledustoidentifyanovelAristaless related homeobox gene (ARX). Inherited and de novo ARX mutations, including missensemutationsandinframeduplications/insertionsleadingtoexpansionsofpolyalaninetractsinARX,werefoundinninefamilialandonesporadiccaseofMR.IncontrasttoothergenesinvolvedinXLMR,ARXexpressionisspecifictothetelencephalonandventralthalamus.Notablythereisanabsenceofexpressioninthecerebellumthroughoutdevelopmentandalsoinadult.TheabsenceofdetectablebrainmalformationsinpatientssuggeststhatARXmayhaveanessentialrole,inmatureneurons,requiredforthedevelopmentofcognitiveabilities.INTRODUCTIONMental retardation (MR) is a frequent cause of serious handicapin children and young adults. It is defined as an overall‘‘intelligence quotient’’ (IQ) lower than 70 associated withfunctional deficits in adaptive behaviour (such as daily-livingskills, social skills and communication), with an onset before18 years (1,2). Moderate to severe MR (IQ<50) is estimated toaffect 0.4–0.8% of the population and the prevalence increasesto 2% if mild MR (50Mendelian Inheritance in Man (OMIM)database identifies close to 1000 entries, many of which areX-linked conditions (XLMR). The prevalence of XLMR hasbeen estimated as 1.8/1000 males with a carrier frequency of2.4/1000 females (3). Historically, XLMR are classified assyndromic (MRXS) and non-specific forms (MRX). For thecloning of the responsible genes, syndromic forms are ingeneral amenable to conventional positional cloning strategiesbecause families that share similar clinical phenotypes can bepooled for linkage analysis to narrow down a candidate interval.However, the situation is more complex for MRX because of theinconsistency of the phenotype and the extensive geneticheterogeneity (4). Although our knowledge of the monogeniccauses of MR is still far from complete, in recent years strikingprogress has been made. It is believed that MRX disorders arecaused by alterations in molecular pathways that are importantfor cognitive functions. Indeed, for MRX, positional cloningefforts have led to the identification of 7 different non-specific