title: Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenstrom macroglobulinemia.
abstract: We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of immunoglobulin A (IgA) and IgG paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. To determine the frequency of P-7 as a paraprotein target in IgM-MGUS and Waldenström macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant P-7 by enzyme-linked immunoabsorbent assay. The specificity of the paraprotein-mediated reaction was shown by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgM-MGUS) of 161 patients (11%) reacted with P-7. Isoelectric focusing and phosphatase treatment showed that P-7 was hyperphosphorylated (pP-7) in all patients with an anti-P-7-specific IgM paraprotein tested. Because only 4 of 200 healthy controls (2%) were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio = 6.2; P = .001) for developing IgM-MGUS/MW. Family analyses showed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgG-MGUS and multiple myeloma, IgM-MGUS/WM is the second neoplasia associated with pP-7 carrier state. The dominant inheritance of pP-7 explains cases of familial IgM-MGUS/WM and enables the identification of family members at increased risk.
authors.affiliation: José-Carreras-Center for Immuno- 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: Alexandra
authors.initials: A
authors.lastname: Wikowicz
authors.forename: Evangelos
authors.initials: E
authors.lastname: Terpos
authors.forename: Marita
authors.initials: M
authors.lastname: Ziepert
authors.forename: Diana
authors.initials: D
authors.lastname: Nikolaus
authors.forename: Yin
authors.initials: Y
authors.lastname: Yang
authors.forename: Natalie
authors.initials: N
authors.lastname: Fadle
authors.forename: Evi
authors.initials: E
authors.lastname: Regitz
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
authors.forename: Steven P
authors.initials: SP
authors.lastname: Treon
authors.forename: Zachary R
authors.initials: ZR
authors.lastname: Hunter
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
mesh_terms: D000918:Antibody Specificity; D001798:Blood Proteins / Q000378:metabolism*; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D010265:Paraproteinemias / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010375:Pedigree; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D001798:Blood Proteins; D007075:Immunoglobulin M; D008565:Membrane Proteins; C406287:STOML2 protein, human