title: Association of a dominantly inherited hyperphosphorylated paraprotein target with sporadic and familial multiple myeloma and monoclonal gammopathy of undetermined significance: a case-control study.
abstract: BACKGROUND
  Chronic antigenic stimulation might have a role in the pathogenesis of monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma. The aim of this study was to search for factors underlying the autoimmunogenicity of paratarg-7, a frequent antigenic target of paraproteins in MGUS and multiple myeloma.
  
  
  METHODS
  Between January, 2005, and February, 2009, serum and peripheral blood cells were obtained from consecutive patients with MGUS or multiple myeloma and healthy blood donors, and paratarg-7 was analysed by DNA sequencing, SDS-PAGE, isoelectric focusing, and western blotting.
  
  
  RESULTS
  Mutations or polymorphisms of paratarg-7 were not noted, but hyperphosphorylation was detected in 35 (13.9%) of 252 patients with MGUS or multiple myeloma, all of whom had an anti-paratarg-7-specific paraprotein. Analysis of eight families showed that hyperphosphorylated paratarg-7 is inherited in a dominant fashion, and that carriers of hyperphosphorylated paratarg-7 have an increased risk of developing MGUS and multiple myeloma (odds ratio [OR] 7.9, 95% CI 2.8-22.6; p=0.0001).
  
  
  CONCLUSIONS
  Familial MGUS and multiple myeloma were associated with a dominant inheritance of hyperphosphorylated paratarg-7, enabling family members at increased risk for MGUS or multiple myeloma to be identified. That only patients with MGUS or multiple myeloma who are carriers of hyperphosphorylated paratarg-7 had a paratarg-7-specific paraprotein suggests that the hyperphosphorylation of paratarg-7 induces auto-immunity and is involved in the pathogenesis of MGUS and multiple myeloma; for example, by chronic antigenic stimulation.
  
  
  BACKGROUND
  Förderverein Krebsforschung Saar-Pfalz-Mosel e.V. (eingetragener Verein: officially registered charity) and HOMFOR (the research programme of the Saarland University Faculty of Medicine).
authors.affiliation: José Carreras Center for Immunotherapy and Gene Therapy, Department of Internal Medicine I, Saarland University Medical School, Homburg (Saar), Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grass
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Preuss
authors.forename: Manfred
authors.initials: M
authors.lastname: Ahlgrimm
authors.forename: Natalie
authors.initials: N
authors.lastname: Fadle
authors.forename: Evi
authors.initials: E
authors.lastname: Regitz
authors.forename: Claudia
authors.initials: C
authors.lastname: Pfoehler
authors.forename: Niels
authors.initials: N
authors.lastname: Murawski
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
mesh_terms: D000328:Adult; D000368:Aged; D001798:Blood Proteins / Q000502:physiology*; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010266:Paraproteins / Q000502:physiology*; D010375:Pedigree; D010766:Phosphorylation
chemical_list: D001798:Blood Proteins; D008565:Membrane Proteins; D010266:Paraproteins; C406287:STOML2 protein, human