Deletion in ADAM17 Connected to Skin, Bowel Disease

Skin, small intestine biopsy samples from affected individuals show paucity of ADAM17 expression

WEDNESDAY, Oct. 19 (HealthDay News) -- A deletion mutation in ADAM17 may be the cause of a neonatal-onset inflammatory skin and bowel disease, according to a study published in the Oct. 20 issue of the New England Journal of Medicine.

Diana C. Blaydon, Ph.D., from Barts and the London School of Medicine and Dentistry, and colleagues performed genetic and immunohistochemical studies in a brother and sister with autosomal recessive neonatal inflammatory skin and bowel lesions. The brother had mild cardiomyopathy, and the sister died suddenly from parvovirus B19-associated myocarditis at age 12. High-throughput sequence technology was used in combination with single-nucleotide polymorphism-homozygosity mapping and targeted sequence capture. Skin samples and blood samples for collection of peripheral-blood mononuclear cells (PBMCs) were obtained from family members and healthy controls. Immunofluorescence staining was performed for biopsy samples of skin and the small intestine, and cytokine levels were measured in PBMC cultures using enzyme-linked immunosorbent assay.

The investigators found that the probable cause of the syndrome was a loss-of-function mutation in ADAM17, which encodes metalloproteinase 17 (tumor necrosis factor α-converting enzyme) and a disintegrin. High levels of lipopolysaccharide-induced production of interleukin-1β and interleukin-6, and impaired release of tumor necrosis factor α were seen in PBMCs obtained from the brother at age 17. ADAM17 was scarcely expressed in skin from the brother and small intestine biopsy samples from both children. PBMCs and keratinocyte lysates from the brother showed a lack of ADAM17 expression in contrast to healthy controls and the unaffected mother.

"We suggest that the deletion mutation in ADAM17 that was present in the homozygous state in both affected children caused their disease," the authors write.

Two authors disclosed financial relationships with pharmaceutical and biotechnology companies.

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