Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy

Apr 01, 2014
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Authors:
Elkan PN, Pierce SB, Segel R, et al.
Citation:
N Engl J Med 2014;370:921-931.
Summary By:
Daniel T. Eitzman, MD

Study Questions:

What is the genetic basis of polyarteritis nodosa (PAN) vasculopathy?

Methods:

Exome and targeted sequencing were performed in persons from multiply affected families and unrelated affected persons. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein.

Results:

Vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2) in all families. ADA2 activity was significantly reduced in serum specimens from patients, and expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein.

Conclusions:

The authors concluded that recessive loss-of-function mutations of ADA2 can cause PAN vasculopathy with highly varied clinical expression.

Perspective:

PAN is a systemic, necrotizing vasculitis, which affects medium and small muscular arteries, resulting in multi-organ ischemic damage. Familial PAN is relatively common in Israeli-Jewish persons of Georgian Caucasus ancestry, and may manifest early in childhood with systemic and cutaneous features. By studying multiple affected families, several mutations were identified in the CECR1 gene, leading to reduced ADA2 activity. These findings provide impetus for future clinical and preclinical studies related to ADA2 in vascular diseases, and also support development of ADA2 therapeutic replacement strategies for affected subjects.

Keywords: Mutation, Biomarkers, Vasculitis, Polyarteritis Nodosa, Epithelial Cells, Pregnancy


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