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Articles by J. A Towbin
Total Records ( 5 ) for J. A Towbin
  T Arimura , N Inagaki , T Hayashi , D Shichi , A Sato , K Hinohara , M Vatta , J. A Towbin , T Chikamori , A Yamashina and A. Kimura
  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.

  X Ma , K Takeda , A Singh , Z. X Yu , P Zerfas , A Blount , C Liu , J. A Towbin , M. D Schneider , R. S Adelstein and Q. Wei
 

Rationale: Germline ablation of the cytoskeletal protein nonmuscle myosin II (NMII)-B results in embryonic lethality, with defects in both the brain and heart. Tissue-specific ablation of NMII-B by a Cre recombinase strategy should prevent embryonic lethality and permit study of the function of NMII-B in adult hearts.

Objective: We sought to understand the function of NMII-B in adult mouse hearts and to see whether the brain defects found in germline-ablated mice influence cardiac development.

Methods and Results: We used a loxP/Cre recombinase strategy to specifically ablate NMII-B in the brains or hearts of mice. Mice ablated for NMII-B in neural tissues die between postnatal day 12 and 22 without showing cardiac defects. Mice deficient in NMII-B only in cardiac myocytes (BMHC/BMHC mice) do not show brain defects. However, BMHC/BMHC mice display novel cardiac defects not seen in NMII-B germline-ablated mice. Most of the BMHC/BMHC mice are born with enlarged cardiac myocytes, some of which are multinucleated, reflecting a defect in cytokinesis. Between 6 to 10 months, they develop a cardiomyopathy that includes interstitial fibrosis and infiltration of the myocardium and pericardium with inflammatory cells. Four of 5 BMHC/BMHC hearts develop marked widening of intercalated discs.

Conclusions: By avoiding the embryonic lethality found in germline-ablated mice, we were able to study the function of NMII-B in adult mice and show that absence of NMII-B in cardiac myocytes results in cardiomyopathy in the adult heart. We also define a role for NMII-B in maintaining the integrity of intercalated discs.

  Z Yang , B. H Funke , L. H Cripe , G. W Vick , D Mancini Dinardo , L. S Pena , R. J Kanter , B Wong , B. H Westerfield , J. J Varela , Y Fan , J. A Towbin and M. Vatta
 

Background— Danon disease is an X-linked dominant disorder characterized by the clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and variable mental retardation. Pathologically, autophagic vacuoles are noted in both skeletal and cardiac muscle. It exhibits an X-linked dominant mode of inheritance, and male carriers are severely affected, whereas female carriers develop milder and later-onset cardiac symptoms. Danon disease has been associated with mutations in the lysosome-associated membrane glycoprotein 2 (LAMP2) gene located at Xq24, typically resulting in splicing defects or protein truncation affecting the LAMP2. Because of its rarity, the full spectrum of genetic mutation resulting in Danon disease has not been elucidated.

Methods and Results— We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selected LAMP2 exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novel Alu-mediated 34-kb microdeletion encompassing the entire 5'-untranslated region and exon 1 of LAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)n simple repeats present in intron 3, which determined a 64-kb and a 58-kb deletion, respectively, thereby ablating exons 4 to 10. Western blot analysis confirmed the absence of LAMP2 in protein extract from lymphocytes of index case 2.

Conclusion— This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1 Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences.

  T. P Singh , L. A Sleeper , S Lipshultz , A Cinar , C Canter , S. A Webber , D Bernstein , E Pahl , J. A Alvarez , J. D Wilkinson , J. A Towbin and S. D. Colan
 

Background— In patients with dilated cardiomyopathy, the magnitude of cardiac remodeling often correlates with the clinical severity of heart failure. We sought to determine whether measures of left ventricular (LV) dilation and systolic dysfunction in children with dilated cardiomyopathy at the time of listing for cardiac transplantation are associated with survival while waiting for and early after transplant.

Methods and Results— We analyzed echocardiographic data obtained within 6 months of listing for heart transplant and clinical data from 261 children with dilated cardiomyopathy who were included in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. Median time to listing after diagnosis was 1.9 months and to transplant after listing was 0.8 months. There were 42 deaths (29 waiting and 13 within 6 months after transplant). We found a significant age-dependent association of LV end-diastolic dimension z score (n=204, 31 deaths) with death controlling for race, transplant status, and medical insurance. The association was strongest for infants younger than 6 months at diagnosis (hazard ratio 1.47, P=0.008) and was not significant in children older than 5 years at diagnosis. A similar interaction was identified between age and LV end-systolic dimension z score (P=0.04). Neither LV function nor mass was associated with death, overall, or in subgroups.

Conclusions— The severity of LV dilation at listing for heart transplant is associated with outcome in infants and young children with dilated cardiomyopathy, whereas the severity of LV systolic dysfunction is not. These findings should be considered in risk stratification of these children at listing.

  S. R Foerster , C. E Canter , A Cinar , L. A Sleeper , S. A Webber , E Pahl , P. F Kantor , J. A Alvarez , S. D Colan , J. L Jefferies , J. M Lamour , R Margossian , J. E Messere , P. G Rusconi , R. E Shaddy , J. A Towbin , J. D Wilkinson and S. E. Lipshultz
  Background—

Myocarditis is a cause of a new-onset dilated cardiomyopathy phenotype in children, with small studies reporting high rates of recovery of left ventricular (LV) function.

Methods and Results—

The presenting characteristics and outcomes of children with myocarditis diagnosed clinically and with biopsy confirmation (n=119) or with probable myocarditis diagnosed clinically or by biopsy alone (n=253) were compared with children with idiopathic dilated cardiomyopathy (n=1123). Characteristics at presentation were assessed as possible predictors of outcomes. The distributions of time to death, transplantation, and echocardiographic normalization in the biopsy-confirmed myocarditis and probable myocarditis groups did not differ (P≥0.5), but both groups differed significantly from the idiopathic dilated cardiomyopathy group (all P≤0.003). In children with myocarditis, lower LV fractional shortening z-score at presentation predicted greater mortality (hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98; P=0.03) and greater LV posterior wall thickness predicted transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02 to 1.35; P=0.03). In those with decreased LV fractional shortening at presentation, independent predictors of echocardiographic normalization were presentation with an LV end-diastolic dimension z-score >2 (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58; P<0.001) and greater septal wall thickness (hazard ratio, 1.16; 95% confidence interval, 1.01 to 1.34; P=0.04).

Conclusions—

Children with biopsy-confirmed or probable myocarditis had similar proportions of death, transplantation, and echocardiographic normalization 3 years after presentation and better outcomes than those of children with idiopathic dilated cardiomyopathy. In children with myocarditis who had impaired LV ejection at presentation, rates of echocardiographic normalization were greater in those without LV dilation and in those with greater septal wall thickness at presentation.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005391.

 
 
 
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