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| Item Type: | Article |
|---|---|
| Title: | Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α |
| Creators Name: | Brooke, M.A., Longhurst, H.J., Plagnol, V., Kirkby, N.S., Mitchell, J.A., Rüschendorf, F., Warner, T.D., 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 |
| Source: | Gut |
| ISSN: | 0017-5749 |
| Publisher: | BMJ Publishing Group |
| Volume: | 63 |
| Number: | 1 |
| 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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