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Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α

Item Type:Article
Title:Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α
Creators Name:Brooke, M.A. and Longhurst, H.J. and Plagnol, V. and Kirkby, N.S. and Mitchell, J.A. and Rüschendorf, F. and Warner, T.D. and Kelsell, D.P. and MacDonald, T.T.
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. 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-{alpha} (cPLA(2)alpha). cPLA(2){alpha} protein expression was undetectable in the gut of both siblings, with platelet aggregation and thromboxane A(2) production, as functional assays for cPLA(2){alpha} 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.
Keywords:Biological Markers, Western Blotting, Case-Control Studies, Nonsense Codon, Enteritis, Fluorescent Antibody Technique, Frameshift Mutation, Genetic Markers, Group IV Phospholipases A2, Homozygote, Intestinal Obstruction, Peptic Ulcer, Single Nucleotide Polymorphism, DNA Sequence Analysis, Sequence Deletion, Siblings
Publisher:BMJ Publishing Group
Page Range:96-104
Date:January 2014
Official Publication:https://doi.org/10.1136/gutjnl-2012-303581
PubMed:View item in PubMed

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