title: Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.
abstract: BACKGROUND
  Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood.
  
  
  METHODS
  We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. 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
  In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein.
  
  
  CONCLUSIONS
  Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Paulina
authors.initials: P
authors.lastname: Navon Elkan
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Pierce
authors.forename: Reeval
authors.initials: R
authors.lastname: Segel
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Judith
authors.initials: J
authors.lastname: Barash
authors.forename: Shai
authors.initials: S
authors.lastname: Padeh
authors.forename: Abraham
authors.initials: A
authors.lastname: Zlotogorski
authors.forename: Yackov
authors.initials: Y
authors.lastname: Berkun
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Press
authors.forename: Masha
authors.initials: M
authors.lastname: Mukamel
authors.forename: Isabel
authors.initials: I
authors.lastname: Voth
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hashkes
authors.forename: Liora
authors.initials: L
authors.lastname: Harel
authors.forename: Vered
authors.initials: V
authors.lastname: Hoffer
authors.forename: Eduard
authors.initials: E
authors.lastname: Ling
authors.forename: Fatos
authors.initials: F
authors.lastname: Yalcinkaya
authors.forename: Ozgur
authors.initials: O
authors.lastname: Kasapcopur
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
authors.forename: Paul
authors.initials: P
authors.lastname: Renbaum
authors.forename: Ariella
authors.initials: A
authors.lastname: Weinberg-Shukron
authors.forename: Elif F
authors.initials: EF
authors.lastname: Sener
authors.forename: Barbara
authors.initials: B
authors.lastname: Schormair
authors.forename: Sharon
authors.initials: S
authors.lastname: Zeligson
authors.forename: Dina
authors.initials: D
authors.lastname: Marek-Yagel
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Amihood
authors.initials: A
authors.lastname: Singer
authors.forename: Alan
authors.initials: A
authors.lastname: Rubinow
authors.forename: Elon
authors.initials: E
authors.lastname: Pras
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
mesh_terms: D000243:Adenosine Deaminase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D005846:Georgia (Republic); D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010488:Polyarteritis Nodosa / Q000235:genetics* / Q000473:pathology; D014421:Turkey
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C408373:ADA2 protein, human; D000243:Adenosine Deaminase