Background/Purpose:

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis. Disease pathogenesis and possible genetic factors are poorly understood.  We identified familial, mostly pediatric PAN, in twenty patients from six families, five of Georgian Jewish and one of German origin. Disease segregation was consistent with autosomal recessive inheritance.  

Methods:

Clinical data was collected from eight medical centers in Israel, Germany and Turkey. Exome sequencing was performed in six patients with familial PAN, four Georgian Jewish and two Germans. Targeted sequencing was done in another thirteen patients with familial PAN and in seventeen single cases: three of Gerogian Jewish and fourteen of Turkish origin. Mutations were assessed by impact on enzymatic activity in patient sera, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. 

Results:

In most patients, disease onset was in early childhood and was most severe in those with onset in infancy. Skin manifestations almost universal: livedo reticularis, nodules, recalcitrant leg ulcers and acral necrosis. Raynaud’s phenomenon, myalgia, arthralgia or arthritis were also common. Systemic involvement included gastrointestinal disease with significant weight loss and intestinal perforation, testicular pain, coronary and renal vasculitis with severe hypertension, peripheral neuropathy and brain strokes. Angiography demonstrated mesenteric, celiac, hepatic, or renal aneurysms, and infarcts in the renal cortex. There was a dramatically beneficial response to anti-TNF alpha blockade; life-saving in some cyclophosphamide refractory patients. All patients had recessive mutations in an immune-related gene, to be named at the meeting. Mutations in this gene have not been previously associated with any human phenotype. All Georgian Jewish cases were homozygous for this mutation, with variable phenotype; The German and the Turkish patients were compound heterozygous for mutations in the same gene. In the endogamous Georgian Jewish population, the allele frequency was 0.05, reflecting high PAN prevalence. The other mutations were private or extremely rare. The missense mutations led to significantly reduced protein activity and secretion both in patient sera and in vitro. Protein activity was significantly reduced in patient sera. 

Conclusion:

Recessive loss-of-function mutations in an immune- related gene lead to PAN. Both population genetics and functional approaches were applied to demonstrate the causality of the founder allele. The mutations identified suggest blood vessels may be particularly vulnerable to impairment of the protein’s catalytic, immune, and growth factor activities. A single-gene defect underlying a systemic vasculitis may provide new insights on disease pathogenesis and possibly help to develop new targeted therapy for PAN and other vasculitides.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-novel-genetic-basis-for-systemic-vasculitis-polyarteritis-nodosa-caused-by-recessive-mutations-in-an-immune-related-gene/