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Abstract Number: 2642

A Novel Genetic Basis For Systemic Vasculitis: Polyarteritis Nodosa Caused By Recessive Mutations In An Immune-Related Gene

Reeval Segel1,2, Pnina Elkan-Navon3, Sarah B. Pierce4, Tom Walsh4, Judith Barash5, Shay Padeh6, Avraham Zlotogorski7, Yackov Berkun8, Isabel Voth9, Philip Hashkes10, Liora Harel11, Eduard Ling12, Fatos Yalcinkaya13, Ozgur Kasapcopur14, Paul F. Renbaum15, Ariella Weinberg-Shukron15, Barbara Schormair16, Mordechai Shohat17, Alan A. Rubinow18, Elon Pras19, Juliane Winkelmann20, Mustafa Tekin21, Yair Anikster22, Mary-Claire King4 and Ephrat Levy-Lahad15, 1Medical Genetics and Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel, 2Hebrew University Medical School, Jerusalem, Israel, 3Pediatrics, Shaare Zedek Medical Center, Jerusalem, Israel, 4Medical Genetics, University of Washington, Seattle, WA, 5Pediatric Day Care, Kaplan Medical Center, Rehovot, Israel, 6Pediatrics, Sheba Medical Center, Ramat Gan, Israel, 7Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, 8Pediatrics, Hadassah Medical Center, Mount Scopus, Jerusalem, Israel, 9Department of Neurology, Technische Universitat Munchen Klinikum rechts der Isar, Munich, Germany, 10Pediatric Rheumatology, Shaare Zedek Medical Center, Jerusalem, Israel, 11Pediatric Rheumatology unit, Schneider Children's Medical Center, Tel Aviv University, Petach Tikvah, Israel, 12Rheumatology Unit, Soroka University Medical Center and Ben-Gurion University, Beer-Sheva, Beer Sheva, Israel, 13Pediatric Nephrology and Rheumatology, Ankara University, Ankara, Turkey, 14Ankara University, Ankara, Turkey, 15Medical Genetics, Shaare Zedek Medical Center, Jerusalem, Israel, 16Helmholtz Zentrum Munchen, Munich, Germany, 17Rafael Recanati medical genetics Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikvah, Israel, 18Hadassah Medical Center, Jerusalem, Israel, 19Institute of Human Genetics, Sheba Medical Center, Ramat Gan, Israel, 20Genetics, Stanford University, San Francisco, CA, 21Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 22Metabolic Disease Unit, Sheba Medical Center, Ramat Gan, Israel

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: genetics, livedo reticularis, pathogenesis, polyarteritis nodosa and vasculitis

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Session Information

Session Title: Vasculitis III

Session Type: Abstract Submissions (ACR)

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.


Disclosure:

R. Segel,
None;

P. Elkan-Navon,
None;

S. B. Pierce,
None;

T. Walsh,
None;

J. Barash,
None;

S. Padeh,
None;

A. Zlotogorski,
None;

Y. Berkun,
None;

I. Voth,
None;

P. Hashkes,
None;

L. Harel,
None;

E. Ling,
None;

F. Yalcinkaya,
None;

O. Kasapcopur,
None;

P. F. Renbaum,
None;

A. Weinberg-Shukron,
None;

B. Schormair,
None;

M. Shohat,
None;

A. A. Rubinow,
None;

E. Pras,
None;

J. Winkelmann,
None;

M. Tekin,
None;

Y. Anikster,
None;

M. C. King,
None;

E. Levy-Lahad,
None.

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