title: Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X).
abstract: Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C>G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C>G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.
authors.affiliation: Department of Genetics and Molecular Pathology, Neurogenetics Laboratory, SA Pathology, Adelaide, Australia.
authors.forename: Tod
authors.initials: T
authors.lastname: Fullston
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.forename: Tracey
authors.initials: T
authors.lastname: Willis
authors.forename: Sunny
authors.initials: S
authors.lastname: Philip
authors.forename: Lesley
authors.initials: L
authors.lastname: MacPherson
authors.forename: Merran
authors.initials: M
authors.lastname: Finnis
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics; D001483:Base Sequence; D002585:Cesarean Section; D002648:Child; D004252:DNA Mutational Analysis; D004827:Epilepsy / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011247:Pregnancy; D017384:Sequence Deletion; D013036:Spasms, Infantile / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C469264:ARX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors