A novel genetic basis for systemic vasculitis: Systemic and cutaneous Polyarteritis Nodosa (PAN) are caused by recessive mutations in an immune-related gene. R. Segel1, S. B. Pierce2, P. Elkan-Navon1, T. Walsh2, S. Padeh3, J. Barash4, A. Zlotogorski5, Y. Y. Berkun5, J. J. Press6, M. Mukamel6, P. J. Hashkes1, E. Ling7, L. L. Harel6, M. Tekin8,9, F. Yalcinkaya8, O. Kasapcopur10, E. F. Emirogullari9, M. K. Lee2, R. E. Klevit2, P. F. Renbaum1, A. Weinberg-Shukron1, S. Zeligson1, D. Marek-Yagel3, M. Shohat6, A. Singer11, E. Pras3, A. A. Rubinow5, Y. Anikster3, M. C. King2, E. Levy-Lahad1 1) Medical Genetics Institute, Shaare Zedek Medical center, Jerusalem, Israel; 2) University of Washington, Seattle, United States; 3) Sheba Medical Center, Tel Hashomer, Israel; 4) Kaplan Medical Center, Rehovoth, Israel; 5) Hadassah Medical Center, Jerusalem, Israel; 6) Schneider Childrens Medical Center, Petach Tikvah, Israel; 7) Soroka Medical Center, Beer Sheva, Israel; 8) Ankara University, Ankara, Turkey; 9) University of Miami, Miami, United States; 10) Istanbul University, Istanbul, Turkey; 11) Barzilai Medical Center, Ashkelon, Israel.
Background: Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis of middle-sized arteries, found in adults and children. Disease pathogenesis is poorly understood. We identified multiple cases of PAN and cutaneous PAN in families and individuals of Georgian-Jewish ancestry, a historically endogamous isolate, consistent with autosomal recessive inheritance. While most cases had childhood onset, those with cutaneous PAN initiated in middle age. Methods: Exome sequencing was carried out for 4 affected individuals from 2 families and targeted sequencing in 16 additional Georgian-Jewish cases, and in 9 Turkish pediatric PAN cases. Mutations were assayed by protein structure analysis, expression in mammalian cells, biophysical analysis of purified protein, and protein activity in patient sera. Results: A founder mutation was identified in an immune-related gene, the only rare, damaging variant homozygous in all 4 exomes. Mutations in this gene have not been previously associated with any human phenotype. All Georgian-Jewish patients were homozygous for this mutation, except for one, who was compound heterozygous for this mutation and another missense mutation. There was a wide range of expressivity and of severity of the vasculitis phenotype in individuals who were homozygous for the same allele. One Turkish case was compound heterozygous for a mutation at the same codon and another missense mutation. In the Georgian Jewish population, the allele frequency was 0.05, reflecting the high prevalence of PAN in this endogamous community. The other mutations were absent both in the general population and in ethnically matched controls. The missense allele leads to loss of function of the protein both in patient sera and in vitro. Protein activity was significantly reduced in patient sera. Expression of mutant proteins in HEK293T cells revealed a significant reduction of secreted protein in the media. Conclusions: We report mutations in a gene not previously associated with any human phenotype as the first genetic cause of systemic vasculitis. 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 loss of this serum protein's activity. They are consistent with PAN being an immune disorder, suggest possible new treatment and offer new opportunities to elucidate the pathogenesis of PAN and other forms of vasculitis.
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