title: ARX spectrum disorders: making inroads into the molecular pathology.
abstract: The Aristaless-related homeobox gene (ARX) is one of the most frequently mutated genes in a spectrum of X-chromosome phenotypes with intellectual disability (ID) as their cardinal feature. To date, close to 100 families and isolated cases have been reported to carry 44 different mutations, the majority of these (59%) being a result of polyalanine tract expansions. At least 10 well-defined clinical entities, including Ohtahara, Partington, and Proud syndromes, X-linked infantile spasms, X-linked lissencephaly with ambiguous genitalia, X-linked myoclonic epilepsy and nonsyndromic intellectual disability have been ascertained from among the patients with ARX mutations. The striking intra- and interfamilial pleiotropy together with genetic heterogeneity (same clinical entities associated with different ARX mutations) are becoming a hallmark of ARX mutations. Although males are predominantly affected, some mutations associated with malformation phenotypes in males also show a phenotype in carrier females. Recent progress in the study of the effect of ARX mutations through sophisticated animal (mice) and cellular models begins to provide crucial insights into the molecular function of ARX and associated molecular pathology, thus guiding future inquiries into therapeutic interventions.
authors.affiliation: Department of Genetics and Molecular Pathology, SA Pathology at the Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia. cheryl.shoubridge@adelaide.edu.au
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
authors.forename: Tod
authors.initials: T
authors.lastname: Fullston
authors.forename: Jozef
authors.initials: J
authors.lastname: Gécz
mesh_terms: D000089662:Doublecortin Protein; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology*; D007515:Islets of Langerhans / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C469264:ARX protein, human; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D014157:Transcription Factors