title: Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.
abstract: OBJECTIVE
  Cryptogenic multifocal ulcerating stenosing enteritis (CMUSE) is an extremely rare, but devastating, disease of unknown aetiology. We investigated the genetic basis of this autosomal recessive condition in a pair of affected siblings who have 40-year histories of catastrophic gastrointestinal and extraintestinal disease.
  
  
  METHODS
  Genome-wide single-nucleotide polymorphism homozygosity mapping in the two affected family members combined with whole-exome sequencing of one affected sibling. This was followed by confirmatory Sanger sequencing of the likely disease-causing sequence variant and functional studies in affected and unaffected family members.
  
  
  RESULTS
  Insertion/deletion variation analysis revealed the presence of a homozygous 4 bp deletion (g.155574_77delGTAA) in the PLA2G4A gene, located in the splice donor site directly after exon 17 (the penultimate exon) of the gene in both affected siblings. This introduces a frameshift of 10 amino acids before a premature stop codon (p.V707fsX10), which is predicted to result in the loss of 43 amino acids (residues 707-749) at the C-terminus of cytosolic phospholipase A2-α (cPLA(2)α). cPLA(2)α protein expression was undetectable in the gut of both siblings, with platelet aggregation and thromboxane A(2) production, as functional assays for cPLA(2)α activity, grossly impaired.
  
  
  CONCLUSIONS
  We have identified mutations in PLA2G4A as a cause of CMUSE in two affected siblings. Further studies are needed to determine if mutations in this gene are also responsible for disease of a similar phenotype in other cases.
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, , London, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brooke
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Longhurst
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.forename: Thomas T
authors.initials: TT
authors.lastname: MacDonald
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D018389:Codon, Nonsense; D004751:Enteritis / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D016368:Frameshift Mutation; D005819:Genetic Markers; D054513:Group IV Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007415:Intestinal Obstruction / Q000209:etiology; D008297:Male; D010437:Peptic Ulcer / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D035781:Siblings
chemical_list: D015415:Biomarkers; D018389:Codon, Nonsense; D005819:Genetic Markers; D054513:Group IV Phospholipases A2