title: Splicing Defects in the AAAS Gene Leading to both Exon Skipping and Partial Intron Retention in a Tunisian Patient with Allgrove Syndrome.
abstract: OBJECTIVE
  Allgrove syndrome is a rare autosomal recessive disorder characterized by the triad of adrenal insufficiency, achalasia, and alacrima. This syndrome is caused by mutations in the AAAS gene. A major splice site mutation c.1331+1G>A was found previously in North African families affected by Allgrove syndrome. In this study, we analyzed in vivo and in silico the effect of this mutation on the splicing process.
  
  
  METHODS
  Using reverse transcriptase-polymerase chain reaction, sequencing and bioinformatics tools, we analyzed all transcripts produced by the AAAS gene containing this splice site mutation.
  
  
  RESULTS
  The altered splicing of mRNA produces two aberrant transcripts: one with exon 14 skipping, the other with concurrent exon 14 skipping and retention of 99 bp of intron 14, both outcomes resulting in frameshifts with a new stop codon generation in the untranslated region of the last exon. Using in silico bioinformatics tools, we demonstrated that this mutation abolishes the splice donor site of exon 14 and activates a new intronic cryptic splice site in intron 14.
  
  
  CONCLUSIONS
  This study demonstrated that a single splicing mutation affects the AAAS transcripts and consequently the ALADIN protein structure and function.
authors.affiliation: Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia.
authors.forename: Fakhri
authors.initials: F
authors.lastname: Kallabi
authors.forename: Bochra
authors.initials: B
authors.lastname: Ben Rhouma
authors.forename: Siwar
authors.initials: S
authors.lastname: Baklouti
authors.forename: Rania
authors.initials: R
authors.lastname: Ghorbel
authors.forename: Rahma
authors.initials: R
authors.lastname: Felhi
authors.forename: Leila
authors.initials: L
authors.lastname: Keskes
authors.forename: Hassen
authors.initials: H
authors.lastname: Kamoun
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D004931:Esophageal Achalasia / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D017354:Point Mutation; D012326:RNA Splicing / Q000235:genetics*; D014416:Tunisia
chemical_list: C416506:AAAS protein, human; D009419:Nerve Tissue Proteins; D028861:Nuclear Pore Complex Proteins