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Circulation Research Sep 2017Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetrical with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients and can be provoked in another third. The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter-defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. and , encoding β-myosin heavy chain and myosin-binding protein C, respectively, are the 2 most common genes involved, together accounting for ≈50% of the HCM families. In ≈40% of HCM patients, the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.
Topics: Animals; Biopsy; Cardiac Imaging Techniques; Cardiomyopathy, Dilated; DNA Mutational Analysis; Genetic Markers; Genetic Predisposition to Disease; Humans; Molecular Diagnostic Techniques; Mutation; Myocardium; Phenotype; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; Ventricular Function, Left
PubMed: 28912181
DOI: 10.1161/CIRCRESAHA.117.311059 -
Journal of Internal Medicine Jun 2020Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but... (Review)
Review
Mitochondrial disease presenting in childhood is characterized by clinical, biochemical and genetic complexity. Some children are affected by canonical syndromes, but the majority have nonclassical multisystemic disease presentations involving virtually any organ in the body. Each child has a unique constellation of clinical features and disease trajectory, leading to enormous challenges in diagnosis and management of these heterogeneous disorders. This review discusses the classical mitochondrial syndromes presenting most frequently in childhood and then presents an organ-based perspective including systems less frequently linked to mitochondrial disease, such as skin and hair abnormalities and immune dysfunction. An approach to diagnosis is then presented, encompassing clinical evaluation and biochemical, neuroimaging and genetic investigations, and emphasizing the problem of phenocopies. The impact of next-generation sequencing is discussed, together with the importance of functional validation of novel genetic variants never previously linked to mitochondrial disease. The review concludes with a brief discussion of currently available and emerging therapies. The field of mitochondrial medicine has made enormous strides in the last 30 years, with approaching 400 different genes across two genomes now linked to primary mitochondrial disease. However, many important questions remain unanswered, including the reasons for tissue specificity and variability of clinical presentation of individuals sharing identical gene defects, and a lack of disease-modifying therapies and biomarkers to monitor disease progression and/or response to treatment.
Topics: Child; Humans; Mitochondria; Mitochondrial Diseases; Mutation; Phenotype
PubMed: 32176382
DOI: 10.1111/joim.13054 -
Biochimica Et Biophysica Acta.... Apr 2022ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of... (Review)
Review
ARPKD is a genetically inherited kidney disease that manifests by bilateral enlargement of cystic kidneys and liver fibrosis. It shows a range of severity, with 30% of individuals dying early on and the majority having good prognosis if they survive the first year of life. The reasons for this variability remain unclear. Two genes have been shown to cause ARPKD when mutated, PKHD1, mutations in which lead to most of ARPKD cases and DZIP1L, which is associated with moderate ARPKD. This mini review will explore the genetics of ARPKD and discuss potential genetic modifiers and phenocopies that could affect diagnosis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Humans; Polycystic Kidney, Autosomal Recessive; Polymorphism, Genetic; Prognosis; Receptors, Cell Surface; Signal Transduction; Transcription Factors
PubMed: 35032595
DOI: 10.1016/j.bbadis.2022.166348 -
Cell May 2015Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV...
Most cancer cells release heterogeneous populations of extracellular vesicles (EVs) containing proteins, lipids, and nucleic acids. In vitro experiments showed that EV uptake can lead to transfer of functional mRNA and altered cellular behavior. However, similar in vivo experiments remain challenging because cells that take up EVs cannot be discriminated from non-EV-receiving cells. Here, we used the Cre-LoxP system to directly identify tumor cells that take up EVs in vivo. We show that EVs released by malignant tumor cells are taken up by less malignant tumor cells located within the same and within distant tumors and that these EVs carry mRNAs involved in migration and metastasis. By intravital imaging, we show that the less malignant tumor cells that take up EVs display enhanced migratory behavior and metastatic capacity. We postulate that tumor cells locally and systemically share molecules carried by EVs in vivo and that this affects cellular behavior.
Topics: Animals; Cell Line, Tumor; Humans; Integrases; Mice; Neoplasm Metastasis; Neoplastic Cells, Circulating; Transport Vesicles
PubMed: 26000481
DOI: 10.1016/j.cell.2015.04.042 -
American Journal of Physiology.... Apr 2019The liver is a critical tissue for maintaining glucose, fatty acid, and cholesterol homeostasis. Primary hepatocytes represent the gold standard for studying the...
The liver is a critical tissue for maintaining glucose, fatty acid, and cholesterol homeostasis. Primary hepatocytes represent the gold standard for studying the mechanisms controlling hepatic glucose, lipid, and cholesterol metabolism in vitro. However, access to primary hepatocytes can be limiting, and therefore, other immortalized hepatocyte models are commonly used. Here, we describe substrate metabolism of cultured AML12, IHH, and PH5CH8 cells, hepatocellular carcinoma-derived HepG2s, and primary mouse hepatocytes (PMH) to identify which of these cell lines most accurately phenocopy PMH basal and insulin-stimulated metabolism. Insulin-stimulated glucose metabolism in PH5CH8 cells, and to a lesser extent AML12 cells, responded most similarly to PMH. Notably, glucose incorporation in HepG2 cells were 14-fold greater than PMH. The differences in glucose metabolic activity were not explained by differential protein expression of key regulators of these pathways, for example glycogen synthase and glycogen content. In contrast, fatty acid metabolism in IHH cells was the closest to PMHs, yet insulin-responsive fatty acid metabolism in AML12 and HepG2 cells was most similar to PMH. Finally, incorporation of acetate into intracellular-free cholesterol was comparable for all cells to PMH; however, insulin-stimulated glucose conversion into lipids and the incorporation of acetate into intracellular cholesterol esters were strikingly different between PMHs and all tested cell lines. In general, AML12 cells most closely phenocopied PMH in vitro energy metabolism. However, the cell line most representative of PMHs differed depending on the mode of metabolism being investigated, and so careful consideration is needed in model selection.
Topics: Acetates; Animals; Cell Line; Cholesterol; Cholesterol Esters; Fatty Acids; Glucose; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin; Lipid Metabolism; Mice; Primary Cell Culture
PubMed: 30694691
DOI: 10.1152/ajpendo.00365.2018 -
Molecular and Cellular Biology 2023During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2"...
During the inflammatory response, macrophage phenotypes can be broadly classified as pro-inflammatory/classically activated "M1", or pro-resolving/alternatively "M2" macrophages. Although the classification of macrophages is general and assumes there are distinct phenotypes, in reality macrophages exist across a spectrum and must transform from a pro-inflammatory state to a proresolving state following an inflammatory insult. To adapt to changing metabolic needs of the cell, mitochondria undergo fusion and fission, which have important implications for cell fate and function. We hypothesized that mitochondrial fission and fusion directly contribute to macrophage function during the pro-inflammatory and proresolving phases. In the present study, we find that mitochondrial length directly contributes to macrophage phenotype, primarily during the transition from a pro-inflammatory to a proresolving state. Phenocopying the elongated mitochondrial network (by disabling the fission machinery using siRNA) leads to a baseline reduction in the inflammatory marker IL-1β, but a normal inflammatory response to LPS, similar to control macrophages. In contrast, in macrophages with a phenocopied fragmented phenotype (by disabling the fusion machinery using siRNA) there is a heightened inflammatory response to LPS and increased signaling through the ATF4/c-Jun transcriptional axis compared to control macrophages. Importantly, macrophages with a fragmented mitochondrial phenotype show increased expression of proresolving mediator arginase 1 and increased phagocytic capacity. Promoting mitochondrial fragmentation caused an increase in cellular lactate, and an increase in histone lactylation which caused an increase in arginase 1 expression. These studies demonstrate that a fragmented mitochondrial phenotype is critical for the proresolving response in macrophages and specifically drive epigenetic changes via lactylation of histones following an inflammatory insult.
Topics: Humans; Histones; Arginase; Lipopolysaccharides; Macrophages; Phenotype; Inflammation; RNA, Small Interfering
PubMed: 37807652
DOI: 10.1080/10985549.2023.2253131 -
Comprehensive Psychiatry Nov 2018In the past 35 years, developmental psychopathology has grown into a flourishing discipline that shares a scientific agenda with contemporary psychiatry. In this...
In the past 35 years, developmental psychopathology has grown into a flourishing discipline that shares a scientific agenda with contemporary psychiatry. In this editorial, which introduces the special issue, we describe the history of developmental psychopathology, including core principles that bridge allied disciplines. These include (1) emphasis on interdisciplinary research, (2) elucidation of multicausal pathways to seemingly single disorders (phenocopies), (3) description of divergent multifinal outcomes from common etiological start points (pathoplasticity), and (4) research conducted across multiple levels of analysis spanning genes to environments. Next, we discuss neurodevelopmental models of psychopathology, and provide selected examples. We emphasize differential neuromaturation of subcortical and cortical neural networks and connectivity, and how both acute and protracted environmental insults can compromise neural structure and function. To date, developmental psychopathology has placed greater emphasis than psychiatry on neuromaturational models of mental illness. However, this gap is closing rapidly as advances in technology render etiopathophysiologies of psychopathology more interrogable. We end with suggestions for future interdisciplinary research, including the need to evaluate measurement invariance across development, and to construct more valid assessment methods where indicated.
Topics: Child; Child Development; Forecasting; Humans; Mental Disorders; Psychiatry; Psychopathology
PubMed: 30415196
DOI: 10.1016/j.comppsych.2018.10.014 -
Neuronal Signaling Sep 2023Mutations in the leucine-rich repeat kinase 2 () gene are associated with familial and sporadic forms of Parkinson's disease (PD). Sporadic PD and LRRK2 PD share main... (Review)
Review
Mutations in the leucine-rich repeat kinase 2 () gene are associated with familial and sporadic forms of Parkinson's disease (PD). Sporadic PD and LRRK2 PD share main clinical and neuropathological features, namely hypokinesia, degeneration of nigro-striatal dopamine neurons and α-synuclein aggregates in the form of Lewy bodies. Animals harboring the most common LRRK2 mutations, i.e. p.G2019S and p.R1441C/G, have been generated to replicate the parkinsonian phenotype and investigate the underlying pathogenic mechanisms. Disappointingly, however, LRRK2 rodents did not consistently phenocopy hypokinesia and nigro-striatal degeneration, or showed Lewy body-like aggregates. Instead, LRRK2 rodents manifested non-motor signs and dysregulated transmission at dopaminergic and non-dopaminergic synapses that are reminiscent of behavioral and functional network changes observed in the prodromal phase of the disease. LRRK2 rodents also manifested greater susceptibility to different parkinsonian toxins or stressors when subjected to dual-hit or multiple-hit protocols, confirming LRRK2 mutations as genetic risk factors. In conclusion, LRRK2 rodents represent a unique tool to identify the molecular mechanisms through which LRRK2 modulates the course and clinical presentations of PD and to study the interplay between genetic, intrinsic and environmental protective/risk factors in PD pathogenesis.
PubMed: 37601008
DOI: 10.1042/NS20220040 -
Frontiers in Immunology 2021Elucidating links between genotype and phenotype in patients with rare inborn errors of immunity (IEIs) provides insights into mechanisms of immune regulation. In many... (Review)
Review
Elucidating links between genotype and phenotype in patients with rare inborn errors of immunity (IEIs) provides insights into mechanisms of immune regulation. In many autosomal dominant IEIs, however, variation in expressivity and penetrance result in complex genotype-phenotype relations, while some autosomal recessive IEIs are so rare that it is difficult to draw firm conclusions. Phenocopies arise when an environmental or non-genetic factor replicates a phenotype conferred by a specific genotype. Phenocopies can result from therapeutic antibodies or autoantibodies that target a protein to replicate aspects of the phenotype conferred by mutations in the gene encoding the same protein. Here, we consider IEIs arising from rare genetic variants in and and compare clinical and laboratory manifestations arising as drug-induced phenocopies (immune related adverse events, IRAEs) in cancer patients treated with immune checkpoint inhibitors (ICI) and identify outstanding questions regarding mechanism of disease.
Topics: CTLA-4 Antigen; Genetic Association Studies; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Variation; Haploinsufficiency; Humans; Immune System Diseases; Immunologic Deficiency Syndromes; Loss of Function Mutation; Phenotype; Programmed Cell Death 1 Receptor
PubMed: 35154081
DOI: 10.3389/fimmu.2021.806043 -
Journal of Medical Genetics Mar 1973
Review
Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Anemia, Aplastic; Anorexia Nervosa; Arm; Cleft Lip; Cleft Palate; Ectromelia; Female; Genes; Heart Defects, Congenital; Hot Temperature; Humans; Phenotype; Pregnancy; Radius; Spine; Syndactyly; Thalidomide; Thrombocytopenia; Thumb; Tibia
PubMed: 4354695
DOI: 10.1136/jmg.10.1.34