👤 Hans H Goebel

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the cardiac myosin binding protein-C (cMyBP-C) encoding gene MYBPC3. In the Netherlands, approximately 25% of patients carry the MYBPC3 Show less

Phenotypic expression of hypertrophic cardiomyopathy (HCM) and disease course are associated with unfavorable metabolic health. We investigated if Western diet (WD) feeding is sufficient to trigger cardiac hypertrophy and dysfunction in heterozygous (HET) Wild-type (WT) and HET mice (3-months-old) were fed a WD or normal chow (NC) for 8 weeks. Metabolomic analyses on serum revealed systemic metabolic derailment in WD-fed WT and HET mice. Strikingly, only WD-fed HET mice developed cardiac hypertrophy and dysfunction, which was not driven by aggravated cardiac myosin binding protein-C haploinsufficiency. WD reduced oxidative phosphorylation and increased toxic lipids in the heart irrespective of genotype. Cardiac proteomic analyses revealed higher abundance of proteins involved in fatty acid oxidation in WD-fed mice, however this increase was blunted in HET compared to WT mice. Accordingly, cardiac metabolomic and lipidomic analyses showed accumulation of acylcarnitines in WD-fed HET vs WT mice. WD feeding triggered cardiac dysfunction and hypertrophy in otherwise phenotype-negative HET Show less

The neuronal ceroid lipofuscinoses (NCL) are genetic degenerative disorders of brain and retina. NCL with juvenile onset (JNCL) is genetically heterogeneous but most frequently caused by mutations of CLN3. Classical juvenile CLN3 includes a rare protracted form, which has previously been linked to autophagic vacuolar myopathy (AVM). Our study investigates the association of AVM with classic, non-protracted CLN3. Evaluation of skeletal muscle biopsies from three, non-related patients with classic, non-protracted and one patient with protracted CLN3 disease by histology, immunohistochemistry, electron microscopy, and Sanger sequencing of the coding region of the CLN3 gene. We identified a novel heterozygous CLN3 mutation (c.1056+34C>A) in one of our patients with classic, non-protracted CLN3 disease. The skeletal muscle of all CLN3 patients was homogeneously affected by an AVM characterized by autophagic vacuoles with sarcolemmal features and characteristic lysosomal pathology. Our observations show that AVM is not an exceptional phenomenon restricted to protracted CLN3 but rather a common feature in CLN3 myopathology. Therefore, CLN3 myopathology should be included in the diagnostic spectrum of autophagic vacuolar myopathies. Show less

A 6-year-old girl had reduced fetal movements, numerous apneic spells, muscle hypotonia, and developmental motor delay. Her muscle biopsy tissue showed variation in myofiber diameters, small minicores by electron microscopy, and near-uniformity of type I fibers. Although no mutations were detected in RYR1, SEPN1, and DMPK genes, the RAPSN gene revealed one known mutation, p.Asn88Lys, from the mother, and one novel mutation, p.Cys366Gly, from the father. Life-saving pyridostigmine treatment suppressed her apneic spells and improved her motor development. Show less

Hypertrophic cardiomyopathy (HCM) has been associated with reduced β-adrenergic receptor (β-AR) signalling, leading downstream to a low protein kinase A (PKA)-mediated phosphorylation. It remained undefined whether all PKA targets will be affected similarly by diminished β-AR signalling in HCM. We aimed to investigate the role of β-AR signalling on regulating myofilament and calcium handling in an HCM mouse model harbouring a gene mutation (G > A transition on the last nucleotide of exon 6) in Mybpc3 encoding cardiac myosin-binding protein C. Cardiomyocyte contractile properties and phosphorylation state were measured in left ventricular permeabilized and intact cardiomyocytes isolated from heterozygous (HET) or homozygous (KI) Mybpc3-targeted knock-in mice. Significantly higher myofilament Ca²⁺sensitivity and passive tension were detected in KI mice, which were normalized after PKA treatment. Loaded intact cardiomyocyte force-sarcomere length relation was impaired in both HET and KI mice, suggesting a reduced length-dependent activation. Unloaded cardiomyocyte function revealed an impaired myofilament contractile response to isoprenaline (ISO) in KI, whereas the calcium-handling response to ISO was maintained. This disparity was explained by an attenuated increase in cardiac troponin I (cTnI) phosphorylation in KI, whereas the increase in phospholamban (PLN) phosphorylation was maintained to wild-type values. These data provide evidence that in the KI HCM mouse model, β-AR stimulation leads to preferential PKA phosphorylation of PLN over cTnI, resulting in an impaired inotropic and lusitropic response. Show less

Hypertrophic cardiomyopathy (HCM), the most common genetic cardiac disorder, is frequently caused by mutations in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Moreover, HCM is the leading cause of sudden cardiac death (SCD) in young athletes. Interestingly, SCD is more likely to occur in male than in female athletes. However, the pathophysiological mechanisms leading to sex-specific differences are poorly understood. Therefore, we studied the effect of sex and exercise on functional properties of the heart and sarcomeres in mice carrying a MYBPC3 point mutation (G > A transition in exon 6) associated with human HCM. Echocardiography followed by isometric force measurements in left ventricular (LV) membrane-permeabilized cardiomyocytes was performed in wild-type (WT) and heterozygous (HET) knock-in mice of both sex (N = 5 per group) in sedentary mice and mice that underwent an 8-week voluntary wheel-running exercise protocol. Isometric force measurements in single cardiomyocytes revealed a lower maximal force generation (F max) of the sarcomeres in male sedentary HET (13.0 ± 1.1 kN/m(2)) compared to corresponding WT (18.4 ± 1.8 kN/m(2)) male mice. Exercise induced a higher F max in HET male mice, while it did not affect HET females. Interestingly, a low cardiac troponin I bisphosphorylation, increased myofilament Ca(2+)-sensitivity, and LV hypertrophy were particularly observed in exercised HET females. In conclusion, in sedentary animals, contractile differences are seen between male and female HET mice. Male and female HET hearts adapted differently to a voluntary exercise protocol, indicating that physiological stimuli elicit a sexually dimorphic cardiac response in heterozygous MYBPC3-targeted knock-in mice. Show less

In childhood the neuronal ceroid lipofuscinoses (NCL) are the most frequent lysosomal diseases and the most frequent neurodegenerative diseases but, in adulthood, they represent a small fraction among the neurodegenerative diseases. Their morphology is marked by: (i) loss of neurons, foremost in the cerebral and cerebellar cortices resulting in cerebral and cerebellar atrophy; (ii) an almost ubiquitous accumulation of lipopigments in nerve cells, but also in extracerebral tissues. Loss of cortical neurons is selective, indiscriminate depletion in early childhood forms occurring only at an advanced stage, whereas loss of neurons in subcortical grey-matter regions has not been quantitatively documented. Among the fourteen different forms of NCL described to date, CLN1 and CLN10 are marked by granular lipopigments, CLN2 by curvilinear profiles (CVPs), CLN3 by fingerprint profiles (FPPs), and other forms by a combination of these features. Among extracerebral tissues, lymphocytes, skin, rectum, skeletal muscle and, occasionally, conjunctiva are possible guiding targets for diagnostic identification, the precise type of NCL then requiring molecular analysis within the clinical and morphological context. Autosomal-recessive adult NCL has been linked molecularly to different childhood forms, i.e. CLN1, CLN5, and CLN6, whilst autosomal-dominant adult NCL, now designated as CLN4, is caused by a newly identified separate gene, DNAJC5. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease. Show less

Perturbations in sarcomeric function may in part underlie systolic and diastolic dysfunction of the failing heart. Sarcomeric dysfunction has been ascribed to changes in phosphorylation status of sarcomeric proteins caused by an altered balance between intracellular kinases and phosphatases during the development of cardiac disease. In the present review we discuss changes in phosphorylation of the thick filament protein myosin binding protein C (cMyBP-C) reported in failing myocardium, with emphasis on phosphorylation changes observed in familial hypertrophic cardiomyopathy caused by mutations in MYBPC3. Moreover, we will discuss assays which allow to distinguish between functional consequences of mutant sarcomeric proteins and (mal)adaptive changes in sarcomeric protein phosphorylation. Show less

The neuronal ceroid lipofuscinoses (NCLs) are a group of severe neurodegenerative diseases with onset usually in childhood and characterised by the intracellular accumulation of autofluorescent storage material. Within the last decade, mutations that cause NCL have been found in six human genes (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8). Mutations in two additional genes cause disease in animal models that share features with NCL-CTSD in sheep and mice and PPT2 in mice. Approximately 160 NCL disease-causing mutations have now been described (listed and fully cited in the NCL Mutation Database, http://www.ucl.ac.uk/ncl/ ). Most mutations result in a classic morphology and disease phenotype, but some mutations are associated with disease that is of later onset, less severe or protracted in its course, or with atypical morphology. Seven common mutations exist, some having a worldwide distribution and others associated with families originating from specific geographical regions. This review attempts to correlate the gene, disease-causing mutation, morphology and clinical phenotype for each type of NCL. Show less

The neuronal ceroid lipofuscinoses (NCLs) represent a group of neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurons and other cells. The main childhood subtypes are infantile (INCL;CLN1), classical late infantile (LINCL;CLN2) and juvenile NCL (JNCL;CLN3), distinguished on the basis of age of onset, clinical course and ultrastructural morphology, and recently genetic analysis. In addition several variant forms of the disease complex have been described as well as a rare adult onset form. Advances in both genetics and biochemistry have led to the identification of the genes for the three main subtypes of childhood NCL and their corresponding protein products and to mapping of two additional genes for two variant forms. The disease causing genes in both INCL and classical LINCL have been shown to encode lysosomal enzymes whilst the JNCL gene codes for a protein whose function is as yet unknown. Show less

The neuronal ceroid lipofuscinoses (NCL) are a relatively frequent group of progressive neurodegenerative disorders in children with similar, but not identical, clinical and morphological features, entailing different clinical groups, some of which have been found to represent different genetic entities, ie, infantile (INCL) or CLN1, late-infantile (LINCL) or CLN2, juvenile (JNCL) or CLN3, and a Finnish variant of LINCL or CLN5. Within the clinical pentad are included seizures, motor disturbances, visual impairment, dementia, and familial occurrence in an autosomal-recessive fashion. The ultrastructure of accruing lipopigments is diagnostically required to recognize an individual patient's NCL by showing granular lipopigments in INCL, curvilinear profiles (with or without fingerprint profiles) in LINCL and fingerprint profiles (with or without curvilinear profiles) in JNCL. Identification of genes for INCL and JNCL, together with electron microscopy in LINCL, allows safe prenatal diagnosis which is still impossible by biochemical techniques, unlike other lysosomal disorders. However, both cause and pathogenesis of the individual forms of NCL are still unknown, and therapy is gravely insufficient. Show less

The neuronal ceroid-lipofuscinoses, a group of progressive neurodegenerative diseases in children and in adults, have now been recognized for some 90 years, and the childhood forms represent one of the largest groups of progressive neurodegenerative diseases in children. Apart from a core group of major clinical forms-the infantile, the late-infantile, the juvenile, and the adult forms--numerous atypical patients afflicted with neuronal ceroid-lipofuscinosis have now been identified, constituting 10% to 20% of all patients with neuronal ceroid-lipofuscinosis. These "atypical" patients have, over the past 10 years, prompted the suggestion of 15 atypical variants or minor syndromes, many of them displaying the lipopigments of classic curvilinear and fingerprint ultrastructure, but others displaying granular osmiophilic deposits. The former lipopigments contain the subunit C of the mitochondrial adenosine triphosphate synthase, but lipopigments of the granular osmiophilic deposits including the classic infantile type Santavuori-Haltia, apparently do not, the latter type exhibiting sphingolipid activator proteins. The nosologic significance of both the subunit C of the adenosine triphosphate synthase and the sphingolipid activator proteins, although they make up a considerable amount of the crude auto-fluorescent lipopigments in neuronal ceroid-lipofuscinosis, is still unclear. In spite of numerous pathogenetic principles invoked, such as a defect in lipid peroxidation, abnormalities of dolichols and dolichol phosphates, and defects in protease inhibitors, precise pathogenesis and etiology of the neuronal ceroid-lipofuscinoses remain elusive. Recent promising molecular genetic studies have, however, revealed the gene for infantile neuronal ceroid-lipofuscinosis, CLN1, on chromosome 1p32; the gene for juvenile neuronal ceroid-lipofuscinosis, CLN3, on chromosome 16p12.1-11.2; and the gene for a Finnish variant of late-infantile neuronal ceroid-lipofuscinosis, CLN5, on chromosome 13q31-32. The genes for classic late-infantile neuronal ceroid-lipofuscinosis, CLN2, and for adult neuronal ceroid-lipofuscinosis, CLN4, have not been located, the former having been excluded from chromosomes 1 and 16. However, the gene products of the normal allelic forms have not yet been identified. A considerable number of sporadic animal models is now available, largely equivalent to the juvenile and infantile forms of neuronal ceroid-lipofuscinosis, with those of the English setter and the South Hampshire sheep evaluated best. Recently, several mouse models have been added to this list of autosomal-recessive models, again the one most thoroughly studied being the motor-neuron disease mouse. Progress has also been made in the prenatal diagnosis of neuronal ceroid-lipofuscinosis: now the infantile, late-infantile, and juvenile forms can be recognized prenatally by a combined genetic and electron microscopic approach. Show less