No abstract

These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Abstract： Hereditary non-polyposis colorectal carcinoma （HNPCC） is one of the prevalent inherited cancers in the general population． Underlying biological process impaired in HNPCC is DNA mismatch repair， which results in microsatellite instability and accumulation of frameshift mutations within the tumor cells． Protein products of the mutant alleles are expected to be the alteredself to the host immune system and become targets for the tumor-specific cytotoxicity． To explore the mechanism for HNPCC tumor cells to escape from the immune surveillance， we investigated the mutations in the beta 2 microglobulin （B 2M） and HLA class 1 genes as well as the microsatellite instabilities in the colorectal cancers． lt was found that either a frame-shift mutation of B2M gene or allele loss of肌A class I genes， which would lead to the extinction of HLA class 1 expression， were more prevalent in the HNPCC tumors than in the non-HNPCC tumors． lnterestingly， none of the tumors exhibited complete loss of B 2M or HLA class 1 genes． These observations strongly suggested that the extinction of HLA class I should be kept incomplete， because the complete loss might activate natural killer cells． Key words： HLA class 1， beta 2 microglobulin， colorectal cancer， HNPCC， immune surveillance Correspondence to： Akinori Kimura， MD， PhD