title: Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene.
abstract: 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.
authors.affiliation: Neurogenetics Laboratory, Genetics and Molecular Pathology, SA Pathology at the Women's and Children's Hospital, Adelaide, South Australia, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Fullston
authors.forename: M
authors.initials: M
authors.lastname: Finnis
authors.forename: A
authors.initials: A
authors.lastname: Hackett
authors.forename: B
authors.initials: B
authors.lastname: Hodgson
authors.forename: L
authors.initials: L
authors.lastname: Brueton
authors.forename: G
authors.initials: G
authors.lastname: Baynam
authors.forename: A
authors.initials: A
authors.lastname: Norman
authors.forename: O
authors.initials: O
authors.lastname: Reish
authors.forename: C
authors.initials: C
authors.lastname: Shoubridge
authors.forename: J
authors.initials: J
authors.lastname: Gecz
mesh_terms: D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication; D015331:Cohort Studies; D017124:Conserved Sequence; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing / Q000379:methods*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors