Hypertrophic cardiomyopathy：from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions.Hypertrophic cardiomyopathy(HCM)was the first cardiac disorder in which a genetic basis was identified and as such,has acted as a paradigm for the study of an inherited cardiac disorder.HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death.HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes.At least ten genes have now been identified,defects in which cause HCM.All of these genes encode proteins which comprise the basic contractile unit of the heart,i.e.the sarcomere.While much is now known about which genes cause disease and the various clinical presentations,very little is known about how these gene defects cause disease,and what factors modify the expression of the mutant genes.Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM,and the role of both environmental and genetic modifying factors.Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function,and will therefore provide new avenues for treating cardiovascular disease in man.     

Hypertrophic cardiornyopathy: from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to     

肥厚型心肌病的致病分子机制研究进展

肥厚型心肌病(Hypertrophic cardiomyopathy,HCM)是以左心室及室间隔不对称肥厚为基本特征的原发性心肌病,其发病率约为0.2%,是青少年和运动员心源性猝死的最常见原因。HCM的发病年龄、发病程度和猝死风险等临床表型具有多样性,通常呈常染色体显性遗传。目前已报道的HCM相关突变超过900种,主要定位在β肌球蛋白重链基因、肌球蛋白结合蛋白C基因、心脏肌钙蛋白T基因等13个心脏肌节蛋白基因;另一方面,越来越多的研究显示线粒体基因突变与HCM发生相关。文章在简单介绍HCM形态学特征及临床表型的基础上,着重综述了HCM的致病分子机制及其最新研究进展。     

LHON: Mitochondrial Mutations and More

Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder leading to severe visual impairment or even blindness by death of retinal ganglion cells (RGCs). The primary cause of the disease is usually a mutation of the mitochondrial genome (mtDNA) causing a single amino acid exchange in one of the mtDNA-encoded subunits of NADH:ubiquinone oxidoreductase, the first complex of the electron transport chain. It was thus obvious to accuse neuronal energy depletion as the most probable mediator of neuronal death. The group of Valerio Carelli and other authors have nicely shown that energy depletion shapes the cell fate in a LHON cybrid cell model. However, the cybrids used were osteosarcoma cells, which do not fully model neuronal energy metabolism. Although complex I mutations may cause oxidative stress, a potential pathogenetic role of the latter was less taken into focus. The hypothesis of bioenergetic failure does not provide a simple explanation for the relatively late disease onset and for the incomplete penetrance, which differs remarkably between genders. It is assumed that other genetic and environmental factors are needed in addition to the 'primary LHON mutations' to elicit RGC death. Relevant nuclear modifier genes have not been identified so far. The review discusses the unresolved problems of a pathogenetic hypothesis based on ATP decline and/or ROS-induced apoptosis in RGCs.     

Intrinsic disorder in pathogenic and non-pathogenic microbes: discovering and analyzing the unfoldomes of early-branching eukaryotes

Parasitic protozoal infections have long been known to cause profound degrees of sickness and death in humans as well as animal populations. Despite the increase in the number of annotated genomes available for a large variety of protozoa, a great deal more has yet to be learned about them, from their fundamental physiology to mechanisms invoked during host-pathogen interactions. Most of these genomes share a common feature, namely a high prevalence of low complexity regions in their predicted proteins, which is believed to contribute to the uniqueness of the individual species within this diverse group of early-branching eukaryotes. In the case of Plasmodium species, which cause malaria, such regions have also been reported to hamper the identification of homologues, thus making functional genomics exceptionally challenging. One of the better accepted theories accounting for the high number of low complexity regions is the presence of intrinsic disorder in these microbes. In this study we compare the degree of disordered proteins that are predicted to be expressed in many such ancient eukaryotic cells. Our findings indicate an unusual bias in the amino acids comprising protozoal proteomes, and show that intrinsic disorder is remarkably abundant among their predicted proteins. Additionally, the intrinsically disordered regions tend to be considerably longer in the early-branching eukaryotes. An analysis of a Plasmodium falciparum interactome indicates that protein-protein interactions may be at least one function of the intrinsic disorder. This study provides a bioinfomatics basis for the discovery and analysis of unfoldomes (the complement of intrinsically disordered proteins in a given proteome) of early-branching eukaryotes. It also provides new insights into the evolution of intrinsic disorder in the context of adapting to a parasitic lifestyle and lays the foundation for further work on the subject.     

Diagnosis and management of brain death.

Finland was the first country in which brain death was legally accepted. Since 1975, 37 cases of brain death had been recorded in a university hospital in Finland, and these were reviewed. The cause for brain death was intracranial bleeding in 32 cases, other cerebrovascular disorder in two, and intracranial neoplasm in three. In 21 brain death was diagnosed clinically. In 16 cases confirmatory investigations (electroencephalography, cerebral angiography) were needed. After brain death had been established artificial support was withdrawn in 15 patients and organ transplantation was carried out in 10. In 12 patients, however, diagnosis of brain death did not influence management, though the heart stopped beating on average 25 hours after diagnosis. The Finnish criteria for brain death seem to be reliable and suitable for routine use.     

Parkinson disease: from pathology to molecular disease mechanisms

Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death.     

Mapping of Calf Death in Japanese Black Cattle

Weak calf syndrome (WCS) is a major cause of calf death in Japanese Black cattle. Among IARS disorders, the isoleucyl-tRNA synthetase c.235G>C mutation has been identified as one of the causes of WCS. However, calf deaths differing from those attributed to IARS disorder has been occurring. To identify other genes potentially responsible for these calf deaths, we constructed three populations of three bulls (Bull-1, -2 and -3) that did not carry the IARS mutation, and dead calves (18, 28, and 31 calves) and healthy cattle (18, 15, and 10 cattle) sired by these bulls. The populations were genotyped using the BovineSNP50 BeadChip, but homozygosity mapping did not detect any associated genomic regions with calf death. Linkage analysis performed using each population as a paternal half-sib family of Bull-1, Bull-2, and Bull-3 revealed that, in the Bull-1 population, calf death was mapped to the 8.94?Mb–14.53?Mb and 29.82?Mb–33.77?Mb regions of BTA29. The findings suggested that the incidence of calf death in calves sired by Bull-1 was a hereditary disease exhibiting a dominant, not recessive, inheritance pattern.     

Motor neuron diseases and neurotoxic substances: A possible link?

The motor neuron diseases (MNDs) are a group of related neurodegenerative diseases that cause the relative selective progressive death of motor neurons. Exploring the molecular mechanisms underlying MND phenotypes has been hampered by their multifactorial nature and high incidence of sporadic cases, although genetic factors are considered to play a considerable role at present. However, environmental factors, especial exposure to neurotoxic substances, could induce neurotoxicity with the same phenotypes of specific MNDs. Organophosphate-induced delayed neuropathy (OPIDN) is a neurodegenerative disorder characterized by ataxia and progression to paralysis, with a concomitant distal axonal degeneration and secondary demyelination of central and peripheral axons. The inhibition and subsequent aging of neuropathy target esterase (NTE) by organophosphate has been proposed to be the initiating event in OPIDN. NTE is characterized to be a lysophospholipase/phospholipase B mostly in the nervous system to regulate phospholipid homeostasis. Brain-specific deletion of mouse NTE contributes to the behavioral defects characterized by neuronal loss. Recently, mutations in human NTE have also been shown to cause a hereditary spastic paraplegia called NTE-related motor neuron disorder with the same characteristics of OPIDN, which supported the role of NTE abnormalities in OPIDN, and raised the possibility that NTE pathway disturbances contribute to other MNDs. Together with the identified association of paraoxonase polymorphisms with amyotrophic lateral sclerosis, there is a possibility that neurotoxic substances contribute to MND in genetically vulnerable people by gene-environment interactions.     

A Missense Mutation in a Highly Conserved Region of CASQ2 Is Associated with Autosomal Recessive Catecholamine-Induced Polymorphic Ventricular Tachycardia in Bedouin Families from Israel

Catecholamine-induced polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death, in response to physical activity or emotional stress. Two modes of inheritance have been described: autosomal dominant and autosomal recessive. Mutations in the ryanodine receptor 2 gene (RYR2), which encodes a cardiac sarcoplasmic reticulum (SR) Ca(2+)-release channel, were recently shown to cause the autosomal dominant form of the disease. In the present report, we describe a missense mutation in a highly conserved region of the calsequestrin 2 gene (CASQ2) as the potential cause of the autosomal recessive form. The CASQ2 protein serves as the major Ca(2+) reservoir within the SR of cardiac myocytes and is part of a protein complex that contains the ryanodine receptor. The mutation, which is in full segregation in seven Bedouin families affected by the disorder, converts a negatively charged aspartic acid into a positively charged histidine, in a highly negatively charged domain, and is likely to exert its deleterious effect by disrupting Ca(2+) binding.     

Bipolar disorder: an update

Bipolar disorder (BPD) is one of the most severe forms of mental illness and is characterized by swinging moods. It affects both sexes equally in all age groups and its worldwide prevalence is approximately 3-5%. The clinical course of illness can vary from a mild depression to a severe form of mania. The condition has a high rate of recurrence and if untreated, it has an approximately 15% risk of death by suicide. It is the third leading cause of death among people aged 15-24 years and is a burden on society and families. The pathophysiology of the disorder is poorly understood. However, a variety of imaging studies suggests the involvement of structural abnormalities in the amygdala, basal ganglia and prefrontal cortex. There are two main biological models that have been proposed for depression. These are called the serotonin and norepinephrine hypotheses. Multiple lines of evidence support both of them. It is a life-long disease and runs in families but has a complex mode of inheritance. Family, twin and adoption studies suggest genetic factors but the candidate susceptibility genes, which when mutated can account for a substantial portion of BPD patients, have not yet been conclusively identified. There have been an increasing number of new generation antidepressant drugs developed to treat BPD. However, lithium salt is only the drug that is most efficient in long-term preventive treatment and it also has an anti-suicidal effect. The condition can be well managed by physicians and psychiatrists along with family and patient education. Identification of risk genes in the future may provide a better understanding of the nature of pathogenesis that may lead to a better therapeutic target.     

Mood stabilizers target cellular plasticity and resilience cascades

Bipolar disorder is a devastating disease with a lifetime incidence of about 1% in the general population. Suicide is the cause of death in 10 to 15% of patients and in addition to suicide, mood disorders are associated with many other harmful health effects. Mood stabilizers are medications used to treat bipolar disorder. In addition to their therapeutic effects for the treatment of acute manic episodes, mood stabilizers are useful as prophylaxis against future episodes and as adjunctive antidepressant medications. The most established and investigated mood-stabilizing drugs are lithium and valproate but other anticonvulsants (such as carbamazepine and lamotrigine) and antipsychotics are also considered as mood stabilizers. Despite the efficacy of these diverse medications, their mechanisms of action remain, to a great extent, unknown. Lithium’s inhibition of some enzymes, such as inositol monophosphatase and gycogen synthase kinase-3, probably results in its mood-stabilizing effects. Valproate may share its anticonvulsant target with its mood-stabilizing target or may act through other mechanisms. It has been shown that lithium, valproate, and/or carbamazepine regulate numerous factors involved in cell survival pathways, including cyclic adenine monophospate response element-binding protein, brain-derived neurotrophic factor, bcl-2, and mitogen-activated protein kinases. These drugs have been suggested to have neurotrophic and neuroprotective properties that ameliorate impairments of cellular plasticity and resilience underlying the pathophysiology of mood disorders. This article also discusses approaches to develop novel treatments specifically for bipolar disorder.     

Could a neurological disease be a part of Mozart's pathography?

As expected, since we recently celebrated the 250th anniversary of birth of Wolfgang Amadeus Mozart, there has been again a renewal of interest in his short but intensive life, as well as in the true reason of his untimely dead. Mozart lived and died in time when the medical knowledge was based mostly on subjective observations, without the established basics of standardized medical terminology and methodology. This leaves a great space for hypothesizing about his health problems, as well as about the cause of his death. The medical academic community attributed to Mozart approximately 150 different medical diagnoses. There is much speculation on the possible causes of Mozart's death: uremia, infection, rheumatic fever, trichinellosis, etc. Recently some authors have raised the question about a possible concomitant neurological disease. According to available records, Mozart has shown some elements of cyclotimic disorder, epilepsy and Gilles de la Tourette syndrome. Furthermore, the finding of a temporal fracture on (allegedly) Mozart's skull, gives a way to speculations about the possibility of a chronic subdural hematoma and its compressive effect on the temporal lobe. Despite numerous theories on Mozart's pathography that also include a concomitant neurological disorder, the medical and history records about Mozart's health status indicate that he probably had suffered from an infective illness, followed most likely by the reactivation of rheumatic fever, which was followed by strong immunologic reaction in the last days of his life. Taking all the above into consideration, it is reasonably to conclude that Mozart's neurological disturbances were caused by the intensity of the infective disease, and not primarily by a neurological disease.     

Mechanisms of neuronal death in disease: defining the models and the players

Dysregulation of life and death at the cellular level leads to a variety of diseases. In the nervous system, aberrant neuronal death is an outstanding feature of neurodegenerative diseases. Since the discovery of the caspase family of proteases, much effort has been made to determine how caspases function in disease, including neurodegenerative diseases. Although many papers have been published examining caspases in neuronal death and disease, the pathways have not been fully clarified. In the present review, we examine the potential players in the death pathways, the current tools for examining these players and the models for studying neurological disease. Alzheimer's disease, the most common neurodegenerative disorder, and cerebral ischaemia, the most common cause of neurological death, are used to illustrate our current understanding of death signalling in neurodegenerative diseases. A better understanding of the neuronal death pathways would provide targets for the development of therapeutic interventions for these diseases.     

Loss of nitric oxide-mediated down-regulation of NMDA receptors in neurofilament aggregate-bearing motor neurons in vitro: implications for motor neuron disease

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder in which excitotoxicity has been implicated as a cause for cell death. To examine neurofilament (NF) aggregate-mediated sensitization of motor neurons to NMDA excitotoxicity, we examined NMDA receptor expression and the impact of NO donors (NOC12 or NOC5) or sodium cyanide (NaCN) on calcium influx and viability in dissociated motor neurons derived from wt and hNFL+/+ (NF aggregate-forming) mice. Alterations in intracellular calcium were assayed using Oregon Green calcium dye and the extent of apoptosis using active caspase-3 immunoreactivity. Although NF aggregate-bearing neurons demonstrated increased intracellular calcium levels and enhanced cell death in response to NMDA receptor activation, this was not associated with increased NMDA receptor expression. The down-regulation of the NMDA receptor using NO donors decreased calcium influx and caspase-3 activation in aggregate-bearing neurons, but had no effect on wt cultures. The converse was observed with NaCN in which intracellular calcium levels increased significantly in wt cultures in association with increased cell death. No effect was observed in aggregate-bearing neurons. These findings suggest that the presence of NF aggregates renders motor neurons more susceptible to NMDA-mediated excitotoxicity, and that this can be reversed by NO.     

Usefulness of pathological examinations of the central nervous system for monitoring and controlling perinatal lamb mortality

Correct diagnosis of cause of death is necessary to suggest the most effective management interventions to reduce perinatal lamb mortality. Haemorrhage on the surface of the brain has been used as a field diagnostic tool to allocate lambs to a cause of death category, but the usefulness of this method was unclear. This study aimed to evaluate whether gross pathology was related to neuronal death and whether haemorrhage of the central nervous system (CNS) was distinct between differing causes of death, enabling indicators to be used in field diagnoses. Lambs dying from natural causes (n = 64) and from euthanasia (n = 7) underwent postmortem examination, then the brain and spinal cord were extracted and examined histologically. Histological changes consistent with neuronal death were not detected in any lamb. Haemorrhage of the meninges and/or parenchyma of the CNS occurred in all lambs. The age of the haemorrhage indicated that it occurred near the time of death in most lambs. Dilation of blood vessels varied in severity but appeared to be unrelated to causal diagnosis, severity of subcutaneous oedema, breathing or milk status. Moderate or severe dilation of blood vessels and haemorrhage of the CNS did not occur in all lambs with alternative clear indicators of dystocia and occurred in all death classifications, so it could not be used as diagnostic indicators for classification of cause of death. Dilation and haemorrhage were unrelated to neuronal damage and may have been artefactual. In conclusion, haemorrhage of the CNS was not indicative of neuronal damage and could not be used to distinguish between lambs with clear indicators of differing causes of death, so it is not recommended as a field diagnostic tool.