ABSTRACT
Paratarg-7 (P-7) is a frequent paraprotein target in monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and Waldenström macroglobulinemia. Patients with P-7-specific paraproteins carry a hyperphosphorylated paratarg-7 (pP-7). Because pP-7 carrier state is dominantly inherited, we determined the paraprotein targets in 4 families with familial MGUS/MM. No antigenic target was identified for the paraproteins from 2 members of one family. Paraproteins from affected members of 2 other families targeted P-7, and paraproteins from 4 affected members of a fourth family targeted P-8, which is encoded by the ATG13 gene. P-8 was hyperphosphorylated in the affected family members (pP-8) and pP-8 carrier state is inherited in a dominant fashion. Six additional autoantigenic nonfamilial paraprotein targets were also hyperphosphorylated in the respective patients compared with normal controls. We conclude that paraproteins of affected members with familial MGUS/MM share family-typical hyperphosphorylated antigens and hyperphosphorylation of paraprotein targets might be a general mechanism underlying the pathogenesis of MGUS/MM.
Subject(s)
Autoantigens/genetics , Autoantigens/metabolism , Multiple Myeloma/genetics , Multiple Myeloma/metabolism , Paraproteins/genetics , Paraproteins/metabolism , Family Health , Female , Genes, Dominant , Heterozygote , Humans , Immunoglobulin A/genetics , Immunoglobulin A/metabolism , Immunoglobulin G/genetics , Immunoglobulin G/metabolism , Immunoglobulin M/genetics , Immunoglobulin M/metabolism , Male , Multiple Myeloma/epidemiology , Pedigree , Phosphorylation/physiology , Prevalence , Protein Array Analysis , Risk FactorsABSTRACT
We describe a family with five cases of multiple myeloma, three cases of monoclonal gammopathy of undetermined significance (MGUS), and five cases of prostate cancer in two generations. The putative progenitor had progeny with two female partners. The progeny had prostate cancer, multiple myeloma, and MGUS.
