Inflammatory Bowel Disease andADAM17Deletion

To the Editor: Blaydon et al. (Oct. 20 issue)1 identify a loss-of-function mutation in ADAM17 as a cause of inflammatory skin and bowel disease in two of three children born to consanguineous parents. We have previously reported an N-ethyl-Nnitrosourea–induced mutation in Adam17, producing a strong dextran sodium sulfate–induced colitis-susceptibility phenotype in mice.2 This mutant mouse (wavedX) was one among many with susceptibility to dextran sodium sulfate caused by monogenic mutations, identified in a panel of 6000 G3 (third-generation post-mutagenesis) animals screened for recessive phenotypes. Like its human counterparts, wavedX also had an epidermal abnormality. Histologic analysis of the guts of wavedX mice is normal without administration of dextran sodium sulfate. Similarly, in the siblings described by Blaydon and colleagues, a trigger was probably necessary to induce intestinal inflammation in early childhood. The study by Blaydon et al. validates forward genetic analysis in the mouse as a tool for identifying susceptibility loci in human inflammatory bowel disease, and it adds to the view that many cases of inflammatory bowel disease may be caused by single-gene mutations affecting any of a large number of target loci. Katharina Brandl, Ph.D.