title: Mutation in the 5' alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome.
abstract: The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley-Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21-Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C > T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5' region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.
authors.affiliation: JC Self Research Institute, Greenwood Genetic Center, SC 29646, USA.
authors.forename: Fatima E
authors.initials: FE
authors.lastname: Abidi
authors.forename: Carlos
authors.initials: C
authors.lastname: Cardoso
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lossi
authors.forename: Robert Brian
authors.initials: RB
authors.lastname: Lowry
authors.forename: Danielle
authors.initials: D
authors.lastname: Depetris
authors.forename: Marie-Geneviève
authors.initials: MG
authors.lastname: Mattéi
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Lubs
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Michel
authors.initials: M
authors.lastname: Fontes
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schwartz
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D041321:Chromosomes, Human, X / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: D009687:Nuclear Proteins; D022821:RNA Splice Sites; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein