Loss of ADAM17 is associated with severe multiorgan dysfunction
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Updated: Apr 15, 2026
In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Robert H J Bandsma1, Harry van Goor2, Michael Yourshaw3
1The Division of Pediatric Gastroenterology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands.
Abstract:
ADAM metallopeptidase domain 17 (ADAM17) is responsible for processing large numbers of proteins. Recently, 1 family involving 2 patients with a homozygous mutation in ADAM17 were described, presenting with skin lesions and diarrhea. In this report, we describe a second family confirming the existence of this syndrome. The proband presented with severe diarrhea, skin rash, and recurrent sepsis, eventually leading to her death at the age of 10 months. We performed exome sequencing and detailed pathological and immunological investigations. We identified a novel homozygous frameshift mutation in ADAM17 (NM_003183.4:c.308dupA) leading to a premature stop codon. CD4(+) and CD8(+) T-cell stimulation assays showed severely diminished tumor necrosis factor-α and interleukin-2 production. Skin biopsies indicated a focal neutrophilic infiltrate and spongiotic dermatitis. Interestingly, the patient developed unexplained systolic hypertension and nonspecific hepatitis with apoptosis. This report provides evidence for an important role of ADAM17 in human immunological response and underscores its multiorgan involvement.
Insights
A mutation in ADAM metallopeptidase domain 17 (ADAM17) causes a severe immune deficiency syndrome. This genetic disorder leads to skin issues, diarrhea, and recurrent infections, impacting multiple organs.
Area of Science:
- Genetics
- Immunology
- Dermatology
Background:
- ADAM metallopeptidase domain 17 (ADAM17) is crucial for processing numerous proteins, including those vital for immune function.
- Previous reports identified a rare syndrome associated with ADAM17 mutations, characterized by skin lesions and diarrhea.
Observation:
- This study details a second family with a novel homozygous frameshift mutation (c.308dupA) in ADAM17.
- The proband exhibited severe diarrhea, rash, recurrent sepsis, hypertension, and hepatitis, succumbing at 10 months.
Findings:
- Exome sequencing confirmed a premature stop codon due to the identified ADAM17 mutation.
- Immunological assays revealed significantly reduced tumor necrosis factor-α and interleukin-2 production upon T-cell stimulation.
- Pathological examination of skin biopsies showed neutrophilic infiltrate and spongiotic dermatitis.
Implications:
- This research confirms ADAM17's critical role in human immune responses and highlights its involvement in multiorgan pathologies.
- Understanding ADAM17 function is vital for diagnosing and potentially treating this severe genetic immunodeficiency syndrome.
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