Correspondence

Inflammatory Bowel Disease and ADAM17 Deletion

N Engl J Med 2012; 366:190January 12, 2012DOI: 10.1056/NEJMc1113859

Article

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-N-nitrosourea–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.
Scripps Research Institute, La Jolla, CA

Wataru Tomisato, Ph.D.
Bruce Beutler, M.D.
University of Texas Southwestern Medical Center, Dallas, TX
bruce.beutler@utsouthwestern.edu

No potential conflict of interest relevant to this letter was reported.

2 References

1. 1

   Blaydon DC, Biancheri P, Di W-L, et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med 2011;365:1502-1508
   Free Full Text | Web of Science | Medline

2. 2

   Brandl K, Sun L, Neppl C, et al. MyD88 signaling in nonhematopoietic cells protects mice against induced colitis by regulating specific EGF receptor ligands. Proc Natl Acad Sci U S A 2010;107:19967-19972
   CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Brandl et al. that there are phenotypic similarities (of gut and skin) between the wavedX mutant mouse and humans harboring ADAM17 mutations. However, in the children in our study involving humans, the onset of inflammation was from day 2 and the “trigger” was unclear, unlike that of the wavedX mouse, which required induction by dextran sodium sulfate. In the human cases, the extensive bacterial cutaneous infections are also problematic. With careful phenotyping and the application of high-throughput sequencing, it is likely that other single-gene defects will be shown to account for other cases of syndromic and nonsyndromic inflammatory bowel disease and other inflammatory conditions. Indeed, the genes encoding the interleukin-10 receptor and the interleukin-36 receptor antagonist have recently been described in inflammatory bowel disease and generalized pustular psoriasis, respectively.1-3

Thomas T. MacDonald, Ph.D.
Barts and the London School of Medicine and Dentistry, London, United Kingdom

John I. Harper, M.D.
Institute of Child Health, London, United Kingdom

David P. Kelsell, Ph.D.
Barts and the London School of Medicine and Dentistry, London, United Kingdom
d.p.kelsell@qmul.ac.uk

Since publication of their article, the authors report no further potential conflict of interest.

3 References

1. 1

   Glocker E-O, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009;361:2033-2045
   Free Full Text | Web of Science | Medline

2. 2

   Marrakchi S, Guigue P, Renshaw BR, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med 2011;365:620-628
   Free Full Text | Web of Science | Medline

3. 3

   Onoufriadis A, Simpson MA, Pink AE, et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011;89:432-437
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Jonathan A. Dyer. (2013) New Findings in Genodermatoses. Dermatologic Clinics 31:2, 303-315