Jop H van Berlo

University of Groningen, Groningen, Province of Groningen, Netherlands

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Publications (10)118.51 Total impact

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    ABSTRACT: The goal of this study was to identify the underlying gene defect in a family with inherited myocardial fibrosis. A large family with an autosomal dominantly inherited form of myocardial fibrosis with a highly malignant clinical outcome has been investigated. Because myocardial fibrosis preceded the clinical and echocardiographic signs, we consider the disease to be a hereditary form of cardiac fibrosis. Twenty-five family members were clinically evaluated, and 5 unaffected and 8 affected family members were included in a genome-wide linkage study. The highest logarithm of the odds (LOD) score (LOD = 2.6) was found in the region of the lamin AC (LMNA) gene. The LMNA mutation analysis, both by denaturing gradient gel electrophoresis and sequencing, failed to show a mutation. Subsequent Southern blotting, complementary deoxyribonucleic acid sequencing, and multiplex ligation-dependent probe amplification analysis, however, revealed a deletion of the start codon-containing exon and an adjacent noncoding exon. In vitro studies demonstrated that the deletion results in the formation of nuclear aggregates of lamin, suggesting that the mutant allele is being transcribed. This novel LMNA deletion causes a distinct, highly malignant cardiomyopathy with early-onset primary cardiac fibrosis likely due to an effect of the shortened mutant protein, which secondarily leads to arrhythmias and end-stage cardiac failure.
    Journal of the American College of Cardiology 07/2007; 49(25):2430-9. · 14.09 Impact Factor
  • New England Journal of Medicine 02/2006; 354(2):209-10. · 54.42 Impact Factor
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    J.H. van Berlo
    01/2006;
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    ABSTRACT: Diseases caused by mutations in lamins A and C (laminopathies) suggest a crucial role for A-type lamins in different cellular processes. Laminopathies mostly affect tissues of mesenchymal origin. As transforming growth factor-beta1 (TGF-beta1) signalling impinges on the retinoblastoma protein (pRB) and SMADs, we tested the hypothesis that lamins modulate cellular responses to TGF-beta1 signalling, via the regulation of these transcription factors in mesenchymal cells. Here, we report that A-type lamins are essential for the inhibition of fibroblast proliferation by TGF-beta1. TGF-beta1 dephosphorylated pRB through PP2A, both of which, we show, are associated with lamin A/C. In addition, lamin A/C modulates the effect of TGF-beta1 on collagen production, a marker of mesenchymal differentiation. Our findings implicate lamin A/C in control of gene activity downstream of TGF-beta1, via nuclear phosphatases such as PP2A. This biological function provides a novel explanation for the observed mesenchymal dysfunction in laminopathies.
    Human Molecular Genetics 11/2005; 14(19):2839-49. · 7.69 Impact Factor
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    ABSTRACT: This study evaluated common clinical characteristics of patients with lamin A/C gene mutations that cause either isolated dilated cardiomyopathy or dilated cardiomyopathy in association with skeletal muscular dystrophy. We pooled clinical data of all published carriers of lamin A/C gene mutations as cause of skeletal and/or cardiac muscle disease and reviewed ECG findings. Cardiac dysrhythmias were reported in 92% of patients after the age of 30 years; heart failure was reported in 64% after the age of 50. Sudden death was the most frequently reported mode of death (46%) in both the cardiac and the neuromuscular phenotype. Carriers of lamin A/C gene mutations often received a pacemaker (28%). However, this intervention did not alter the rate of sudden death. Review of the ECG findings typically showed a low amplitude P wave and prolongation of the PR interval with a narrow QRS complex. This meta-analysis suggests that cardiomyopathy due to lamin A/C gene mutations portends a high risk of sudden death, and that this risk does not differ between subjects with predominantly cardiac or neuromuscular disease. This implies then that all carriers of a lamin A/C gene mutation need to be carefully screened with particular emphasis also on tachyarrhythmias. Prospective studies are needed to evaluate risk stratification and proper treatment strategies.
    Journal of Molecular Medicine 02/2005; 83(1):79-83. · 4.77 Impact Factor
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    ABSTRACT: Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF. In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction. This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.
    Circulation 12/2004; 110(19):3121-8. · 15.20 Impact Factor
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    Jop H van Berlo, Denis Duboc, Yigal M Pinto
    European Heart Journal 06/2004; 25(10):812-4. · 14.72 Impact Factor
  • Neuromuscular Disorders 09/2003; 13(6):508-15. · 3.46 Impact Factor
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    Jop H van Berlo, Yigal M Pinto
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    ABSTRACT: Since the discovery of the polymorphism in the angiotensin converting enzyme (ACE) and the consequences of this polymorphism on the activity levels of the enzyme, numerous association studies have been performed. However, these investigations do not often adhere to the most stringent criteria for such studies. The initial study reporting a positive association of the ACE polymorphism and myocardial infarction showed an increased risk of the DD genotype. This initial association was eventually refuted by a large, well conducted association study, which found a risk ratio of 1.02 after combining their own data with all published data. Although such large, well conducted association studies have not been performed in left ventricular (LV) hypertrophy, the association between DD genotype and hypertrophy is more convincing with a 192% excess risk of LV hypertrophy in untreated hypertensives. The role of ACE genotype in LV growth is well established, especially in athletes. In heart failure, large studies or meta-analyses have not been performed, because most studies have selected different end-points. This hampers a proper meta-analysis of the results obtained in associations with heart failure. As most association studies do not fulfill the criteria for good association studies and use too small sample sizes, it remains important to perform a meta-analysis to add meaning to the results of such studies. Above all, it is important to obey the rules set for association studies, large sample size, small P values, report associations that make biological sense and alleles that affect the gene product in a physiologically meaningful way.
    The International Journal of Biochemistry & Cell Biology 07/2003; 35(6):932-43. · 4.15 Impact Factor
  • Jop H. van Berlo, Yigal M. Pinto
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    ABSTRACT: It is obvious to assume that diseases that affect skeletal muscle also affect the heart. Indeed, different myopathies share common cardiac abnormalities. While many different skeletal myopathies can be recognized, only a few different types of cardiomyopathies can be clinically distinguished. This suggests that different skeletal myopathies cause actually quite similar cardiac abnormalities. The reason for this is not clear. It might indicate that the underlying defects in skelatal myopathies all induce common pathways in the heart despite their underlying different pathobiological mechanisms. This probably reflects the very different capacities of skeletal muscle and cardiac muscle. A very important difference between cardiac and skeletal muscle is that unlike the heart, skeletal muscle can be electrically activated only by neurons. Another important difference is the existence of a specialized conduction system within the heart. A third important difference is the type of fibers that make up the contractile elements. The skeletal muscles are all composed of a mixture of fast and slow fibers.Fast fi bers contain large amounts of glycolytic enzymes, have an extensive sarcoplasmic reticulum, and have less blood supply and are therefore ideal for fast contraction with great strength of contraction. Slow fi bers contain large amounts of mitochondria, have a more extended blood supply, and contain myoglobin for oxygen storage, which makes these fi bers red. The heart is built up of striated muscle fi bers, similar to skeletal muscle, but consists of single cardiac myocytes that can pass through electrical signals via the intercalated disc.