Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α
- Matthew A Brooke1,
- Hilary J Longhurst2,
- Vincent Plagnol3,
- Nicholas S Kirkby4,5,
- Jane A Mitchell5,
- Franz Rüschendorf6,
- Timothy D Warner4,
- David P Kelsell1,
- Thomas T MacDonald1
- 1Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 2Department of Clinical Immunology, Barts Health NHS Trust, London, UK
- 3Department of Genetics, University College London, London, UK
- 4William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 5National Heart and Lung Institute, Imperial College, London, UK
- 6Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
- Correspondence to Professor Thomas T MacDonald, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Newark St, London E1 4AD, UK;
- Received 12 October 2012
- Revised 20 November 2012
- Accepted 21 November 2012
- Published Online First 25 December 2012
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.
Design 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 (cPLA2α). cPLA2α protein expression was undetectable in the gut of both siblings, with platelet aggregation and thromboxane A2 production, as functional assays for cPLA2α 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.