title: Autism and nonsyndromic mental retardation associated with a de novo mutation in the NLGN4X gene promoter causing an increased expression level.
abstract: BACKGROUND
  Pathogenic mutations in the X-linked Neuroligin 4 gene (NLGN4X) in autism spectrum disorders (ASDs) and/or mental retardation (MR) are rare. However, nothing is known regarding a possible altered expression level of NLGN4X that would be caused by mutations in regulatory sequences. We investigated this issue by analyzing these regions in patients with ASDs and no mutation in the NLGN4X coding sequence.
  
  
  METHODS
  We studied 96 patients who met all DSM-IV criteria for autism. The entire coding sequence and the regulatory sequences of the NLGN4X gene were analyzed by polymerase chain reaction and direct sequencing.
  
  
  RESULTS
  We identified a de novo 1 base pair (-335G>A) substitution located in the promoter region in a patient with autism and nonsyndromic profound MR. Interestingly, this variation is associated with an increased level of the NLGN4X transcript in the patient compared with male control subjects as well as his father. Further in vitro luciferase reporter and electrophoretic mobility shift assays confirmed, respectively, that this mutation increases gene expression and is probably caused by altered binding of transcription factors in the mutated promoter sequence.
  
  
  CONCLUSIONS
  This result brings further insight about the phenotypic spectrum of NLGN4X mutations and suggests that the analysis of the expression level of NLGN4X might detect new cases.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM U930), Tours, France. daoud_h@med.univ-tours.fr
authors: Hussein
authors: H
authors: Daoud
authors: Frédérique
authors: F
authors: Bonnet-Brilhault
authors: Sylviane
authors: S
authors: Védrine
authors: Marie-Véronique
authors: MV
authors: Demattéi
authors: Patrick
authors: P
authors: Vourc'h
authors: Nadia
authors: N
authors: Bayou
authors: Christian R
authors: CR
authors: Andres
authors: Catherine
authors: C
authors: Barthélémy
authors: Frédéric
authors: F
authors: Laumonnier
authors: Sylvain
authors: S
authors: Briault
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D001523:Mental Disorders / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; C430845:NLGN4X protein, human; D012333:RNA, Messenger