title: Decreased expression of GRAF1/OPHN-1-L in the X-linked alpha thalassemia mental retardation syndrome.
abstract: BACKGROUND
  ATRX is a severe X-linked disorder characterized by mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassemia. The disease is caused by mutations in ATRX gene, which encodes a protein belonging to the SWI/SNF DNA helicase family, a group of proteins involved in the regulation of gene transcription at the chromatin level. In order to identify specific genes involved in the pathogenesis of the disease, we compared, by cDNA microarray, the expression levels of approximately 8500 transcripts between ATRX and normal males of comparable age.
  
  
  METHODS
  cDNA microarray was performed using total RNA from peripheral blood mononuclear cells of ATRX and normal males. Microarray results were validated by quantitative real-time polymerase chain reaction.
  
  
  RESULTS
  cDNA microarray analysis showed that 35 genes had a lower expression (30-35% of controls) while 25 transcripts had a two-fold higher expression in comparison to controls. In the microarray results the probe for oligophrenin-1, a gene known for its involvement in mental retardation, showed a decreased hybridization signal. However, such gene was poorly expressed in blood mononuclear cells and its decrease was not confirmed in the quantitative real-time RT-PCR assay. On the other hand, the expression of an homologous gene, the GTPase regulator associated with the focal adhesion kinase 1/Oligophrenin-1-like (GRAF1/OPHN-1-L), was relatively high in blood mononuclear cells and significantly decreased in ATRX patients. The analysis of the expression pattern of the GRAF1/OPHN-1-L gene in human tissues and organs revealed the predominant brain expression of a novel splicing isoform, called variant-3.
  
  
  CONCLUSIONS
  Our data support the hypothesis of a primary role for altered gene expression in ATRX syndrome and suggest that the GRAF1/OPHN-1-L gene might be involved in the pathogenesis of the mental retardation. Moreover a novel alternative splicing transcript of such gene, predominantly expressed in brain tissues, was identified.
authors.affiliation: Laboratorio sui Sistemi Complessi, Scuola Superiore di Catania, University of Catania, Catania, Italy. condorda@unict.it.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Barresi
authors.forename: Angela
authors.initials: A
authors.lastname: Ragusa
authors.forename: Marco
authors.initials: M
authors.lastname: Fichera
authors.forename: Nicolò
authors.initials: N
authors.lastname: Musso
authors.forename: Lucia
authors.initials: L
authors.lastname: Castiglia
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Rappazzo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Travali
authors.forename: Teresa
authors.initials: T
authors.lastname: Mattina
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Guido
authors.initials: G
authors.lastname: Cocchi
authors.forename: Daniele F
authors.initials: DF
authors.lastname: Condorelli
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing; D002648:Child; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D013577:Syndrome; D017085:alpha-Thalassemia / Q000235:genetics*
chemical_list: C115971:ARHGAP26 protein, human; D020690:GTPase-Activating Proteins; D012313:RNA