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Gut. 2014 Jan;63(1):96-104. doi: 10.1136/gutjnl-2012-303581. Epub 2012 Dec 25.

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

Author information

1
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, , London, UK.

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-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.

KEYWORDS:

Gene Mutation; Inflammatory Bowel Disorders; Non-Steroidal Anti-Inflammatory Drugs

PMID:
23268370
DOI:
10.1136/gutjnl-2012-303581
[Indexed for MEDLINE]

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