ASSOCIATE EDITORS Frank A. Anania, Atlanta, GA Jorge A. Bezerra, Cincinnati, OH Raymond T. Chung, Boston, MA Eithan Galun, Jerusalem, Israel Guadalupe Garcia-Tsao, New Haven, CT Stephen A. Harrison, Fort Sam Houston, TX Brett Lindenbach, New Haven, CT Jacquelyn Maher, San Francisco, CA Wajahat Mehal, New Haven, CT Lola M. Reid, Chapel Hill, NC Mario Strazzabosco, New Haven, CT Norah Terrault, San Francisco, CA Snorri S. Thorgeirsson, Bethesda, MD Michael Trauner, Vienna, Austria

Review of recent research on hepatitis C therapy for 54th annual meeting of the American association for the study of liver diseases

Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.

http://www.euratrans.eu/index.php?view=article&catid=12:news-items&id=977:rbm20-a-gene-for-hereditary-cardiomyopathy-regulates-titin-splicing&format=pdf

RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing

BACKGROUND Congenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest. METHODS Homozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation. RESULTS Phosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls. CONCLUSIONS Phosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.)

/pdf/multiple-phenotypes-in-phosphoglucomutase-1-deficiency-zshkzxgmxh.pdf

Multiple Phenotypes in Phosphoglucomutase 1 Deficiency

The myosin phosphatase targeting protein (MYPT) family: a regulated mechanism for achieving substrate specificity of the catalytic subunit of protein phosphatase type 1δ.

Alternative splicing (AS) of protein-coding messenger RNAs is an essential regulatory mechanism in eukaryotic gene expression that controls the proper function of proteins. It is also implicated in the physiological regulation of mitochondria and various ion channels. Considering that mis-splicing can result in various human diseases by modifying or abrogating important physiological protein functions, a fine-tuned balance of AS is essential for human health. Accumulated data highlight the importance of alternatively spliced isoforms in various diseases, including neurodegenerative disorders, cancer, immune and infectious diseases, cardiovascular diseases, and metabolic conditions. However, basic understanding of disease mechanisms and development of clinical applications still require the integration and interpretation of physiological roles of AS. This review discusses the roles of AS in health and various diseases, while highlighting potential AS-targeting therapeutic applications.

Alternative splicing isoforms in health and disease

Aims Z-band alternatively spliced PDZ-motif protein (ZASP)/Cypher is a Z-disc component of which several dilated cardiomyopathy (DCM)-associated mutations have been reported. Most of the mutations were found in exons 4 and 10 of ZASP/Cypher gene LDB3 and both exons were expressed preferentially in the heart. The aim of this study was to investigate the functional alteration of ZASP/Cypher caused by the DCM-associated mutations.

Methods and results The yeast-two-hybrid method was used to identify the protein bound to a domain encoded by exon 4 of LDB3 . Interaction of ZASP/Cypher with the binding protein was investigated in relation to the functional alterations caused by LDB3 mutations. Localization of the ZASP/Cypher-binding protein was examined at the cellular level in rat cardiomyocytes. Phosphoglucomutase 1 (PGM1), a metabolic enzyme involved in glycolysis and gluconeogenesis, was identified as a protein interacting with ZASP/Cypher. PGM1 bound to ZASP/Cypher at the domains encoded by exons 4 and 10. Two LDB3 mutations in exon 4 (Ser189Leu and Thr206Ile) and another mutation in exon 10 (Ile345Met) reduced the binding to PGM1. PGM1 showed diffuse localization in the cytoplasm of rat cardiomyocytes under standard culture conditions, and distribution at the Z-discs was observed under stressed culture conditions. Binding of endogenous PGM1 and ZASP/Cypher was found to be enhanced by stress in rat cardiomyocytes.

Conclusion ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress. The impaired binding of PGM1 to ZASP/Cypher might be involved in the pathogenesis of DCM.

Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.

Heart-specific Small Subunit of Myosin Light Chain Phosphatase Activates Rho-associated Kinase and Regulates Phosphorylation of Myosin Phosphatase Target Subunit 1

Hypertrophic cardiomyopathy (HCM) is a heart muscle disease characterized by hypertrophy and diastolic dysfunction of cardiac ventricles It is suggested that one possible aetiology of HCM is the hepatitis C virus (HCV) infection, but molecular mechanisms underlying development of HCV-associated HCM (HCV-HCM) remains unknown Because the human leucocyte antigen (HLA) molecule is involved in the control of progression/suppression of viral infection, extensive HLA allelic diversity may modulate the post-infectious course of HCV and pathogenesis of HCV-HCM Here we undertook a case-control study with 38 patients with HCV-HCM and 132 unrelated healthy controls to reveal the potential impact of polymorphisms in seven classical and two non-classical HLA genes on the pathogenesis of HCV-HCM It was found that DPB1*0401 and DPB1*0901 were significantly associated with increased risk to HCV-HCM in dominant model (P < 0028, OR = 394, 95% confidence interval (CI) = 119, 1302) and in recessive model (P < 0007, OR = 985, 95% CI = 183, 5304), respectively The disparity in the gene-dose effect by two susceptible DPB1 alleles may be attributable to the difference between the susceptible (36 A and 55 A) and resistant (8L, 9F, 11G, 57E and 76M) residue-combination consisting of DPbeta anchor pocket for antigenic peptide-binding These results implied that the HLA-DP molecules with specificity pocket appropriate for HCV antigen(s) might confer the progressive process of HCM among the HCV-infected individuals

HLA‐DPβ chain may confer the susceptibility to hepatitis C virus‐associated hypertrophic cardiomyopathy

The human leukocyte antigen (HLA) complex locus has shaped a framework for evolutionary processes because of the dense clustering and strong linkage disequilibrium (LD) of polymorphic genes. Although the landscape of LD among conventional single-nucleotide polymorphisms (SNPs) has been described, the data on the lineage of major histocompatibility complex (MHC) haplotype are limited to pairwise comparisons of several haplotypes in Caucasoid populations. Multi-allelic markers, including microsatellite markers, may provide us with a larger power to analyze the MHC haplotype lineage because the mutation rate of microsatellite exceeds that of SNPs by several orders of magnitude. In this study, we investigated the complex structure of repeat motifs in a microsatellite to figure out the structural lineage of HLA-Cw/-B segments in Japanese. It was found that the genetic differences of HLA-Cw/-B haplotype lineage were reflected by repeat motif patterns at C1_2_5 locus, suggesting that unique mutational dynamics of microsatellites may be a useful marker to chase the haplotype lineage.

/pdf/complex-divergence-at-a-microsatellite-marker-c1-2-5-in-the-58m68rxcpp.pdf

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype

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Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy.

Heart-specific Small Subunit of Myosin Light Chain Phosphatase Activates Rho-associated Kinase and Regulates Phosphorylation of Myosin Phosphatase Target Subunit 1

HLA‐DPβ chain may confer the susceptibility to hepatitis C virus‐associated hypertrophic cardiomyopathy

Complex divergence at a microsatellite marker C1_2_5 in the lineage of HLA-Cw/-B haplotype