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1.
Mol Biol Rep ; 51(1): 883, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39088020

RESUMO

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. Acquired and inherited prothrombotic conditions are the most common risk factors for CVST. Sometimes, an etiology is not found. Wide utilization of next generation sequencing technologies in clinical practice may lead to identification of risk factors other than those classically associated with CVST. METHOD AND RESULTS: This retrospective clinical-laboratory observational study has a reference patient who presented with CVST as an adolescent. Work up for prothrombotic conditions showed high homocysteine level secondary to homozygosity for a common polymorphism, c.677 C > T in the methylenetetrahydrofolate reductase (MTHFR) gene. His older unaffected brother has a similar MTHFR genotype and high homocysteine. The whole exome sequencing revealed a likely pathogenic variant in the sodium voltage gated channel, alpha subunit 1(SCN1A) gene. CONCLUSION: CVST is a multifactorial disease. Prothrombotic conditions are the most common risk factors for CVST. High homocysteine due to the common MTHFR polymorphisms was previously attributed to various thrombotic conditions including CVST. Although high homocysteine due to MTHFR polymorphism may be a contributing factor, additional risk factors such as blood flow abnormalities during SCN1A related seizures may be needed for thrombosis.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2) , Canal de Sódio Disparado por Voltagem NAV1.1 , Trombose dos Seios Intracranianos , Humanos , Trombose dos Seios Intracranianos/genética , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adolescente , Estudos Retrospectivos , Predisposição Genética para Doença , Fatores de Risco , Homocisteína/sangue , Sequenciamento do Exoma/métodos , Polimorfismo de Nucleotídeo Único/genética
2.
Basic Res Cardiol ; 118(1): 46, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37923788

RESUMO

Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.


Assuntos
Insuficiência Cardíaca , Animais , Camundongos , Ratos , Cardiomegalia , Proteínas de Ligação a DNA/metabolismo , Insuficiência Cardíaca/metabolismo , Mitocôndrias/metabolismo , Proteínas Musculares/genética , Miócitos Cardíacos/metabolismo , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/farmacologia , RNA Mensageiro/metabolismo , RNA Mensageiro/farmacologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/farmacologia
3.
Am J Med Genet A ; 191(4): 1089-1093, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36579410

RESUMO

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism. We describe a patient identified through newborn screening in which the diagnosis of MADD was confirmed based on metabolic profiling, but clinical molecular sequencing of ETFA, ETFB, and ETFDH was normal. In order to identify the genetic etiology of MADD, we performed whole genome sequencing and identified a novel homozygous promoter variant in ETFA (c.-85G > A). Subsequent studies showed decreased ETFA protein expression in lymphoblasts. A promoter luciferase assay confirmed decreased activity of the mutant promoter. In both assays, the variant displayed considerable residual activity, therefore we speculate that our patient may have a late onset form of MADD (Type III). Our findings may be helpful in establishing a molecular diagnosis in other MADD patients with a characteristic biochemical profile but apparently normal molecular studies.


Assuntos
Proteínas Ferro-Enxofre , Deficiência Múltipla de Acil Coenzima A Desidrogenase , Recém-Nascido , Humanos , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Flavoproteínas Transferidoras de Elétrons/genética , Aminoácidos/genética , Homozigoto , Proteínas Ferro-Enxofre/genética , Mutação
4.
Hum Mutat ; 39(4): 461-470, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29282788

RESUMO

Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile-onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17-related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early-onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late-onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis.


Assuntos
DNA Mitocondrial/genética , Transtornos Heredodegenerativos do Sistema Nervoso , Hepatopatias , Proteínas de Membrana/genética , Doenças Mitocondriais , Proteínas Mitocondriais/genética , Doenças do Sistema Nervoso Periférico , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Humanos , Fígado/metabolismo , Hepatopatias/diagnóstico , Hepatopatias/genética , Hepatopatias/metabolismo , Mitocôndrias/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Mutação , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/metabolismo
5.
Dev Neurosci ; 40(4): 337-343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30391947

RESUMO

BACKGROUND: The pathophysiology of intraventricular hemorrhage (IVH) is multifactorial. This study attempts to identify genetic and clinical factors contributing to IVH in newborns with a focus on those born ≤28 weeks of gestation. METHODS: This was a prospective study of 382 consecutive newborns admitted to the neonatal intensive care unit. DNA purification was conducted using standard methods. TaqMan SNP assays were conducted for functional polymorphisms in VEGF (RS699947, RS2010963, RS3025039, and RS1570360) and MMP2 (RS243685 and RS2285053) genes. An RFLP assay was done for a polymorphism in MMP9 (RS3918242). RESULTS: The GG genotype in VEGF RS1570360 (p = 0.013) and the CC genotype in VEGF RS699947 (p = 0.036) were associated with a lower incidence of IVH amongst newborns ≤28 weeks of gestation. Chorioamnionitis, Caucasian race, and patent ductus arteriosus were associated with a higher incidence of IVH. A binary logistic regression analysis of clinical and SNP data that was significant from bivariate analysis demonstrated that VEGF RS1570360 was significantly associated with IVH (p = 0.017). CONCLUSION: This study demonstrated that the GA/AA genotype in VEGF RS1570360 and the AA/AC genotype in VEGF RS699947 were associated with higher incidence rates of IVH in newborns ≤28 weeks of gestation. A future study is warranted to comprehensively examine VEGF polymorphisms in association with IVH.


Assuntos
Hemorragia Cerebral/genética , Predisposição Genética para Doença/genética , Metaloproteinases da Matriz/genética , Fator A de Crescimento do Endotélio Vascular/genética , Feminino , Genótipo , Humanos , Lactente Extremamente Prematuro/crescimento & desenvolvimento , Recém-Nascido , Masculino , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Estudos Prospectivos
6.
Am J Med Genet A ; 164A(7): 1815-20, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24700535

RESUMO

Homozygous or compound heterozygous microdeletion of 15q13.3 region is a rare but clinically recognizable syndrome manifested by profound intellectual disability, muscular hypotonia, intractable seizures, and visual impairment. We identified a compound heterozygous 15q13.3 microdeletion in a 23-month-old girl with global developmental delay, generalized muscular hypotonia, and visual dysfunction. The larger deletion was approximately 1.28 Mb in size and contained seven genes including the TRPM1 and CHRNA7, while the smaller deletion was estimated to be 410 Kb in size and contained only CHRNA7. Compound heterozygous 15q13.3 microdeletion is extremely rare and to the best of our knowledge only two such patients have been reported in literature thus far. The findings in our patient suggest that the pathogenesis of visual dysfunction, which is a consistent finding in homozygous/compound heterozygous 15q13.3 microdeletion depends upon the size of microdeletion. Homozygous loss of TRPM1 likely causes retinal dysfunction while homozygous loss of CHRNA7 alone may lead to visual impairment by cortical mechanisms.


Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Estudos de Associação Genética , Heterozigoto , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Convulsões/diagnóstico , Convulsões/genética , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Hipotonia Muscular , Transtornos da Visão
8.
Mol Syndromol ; 15(5): 403-408, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39359947

RESUMO

Introduction: EEF2 encodes eukaryotic elongation factor 2 which catalyzes the elongation phase of protein translation. It is ubiquitously expressed and important for neuronal function. EEF2 was first associated with adult-onset spinocerebellar ataxia type 26 (SCA26). A novel neurodevelopmental disorder associated with de novo heterozygous variants in EEF2 has been described. Only 6 patients have been described in the literature thus far. A 9-year-old child with de novo novel missense variant is described here. EEF2-related neurodevelopmental disorder appears to be clinically recognizable. Case Presentation: A nine-year-old male with autism spectrum disorder was referred for genetic evaluation. On examination, he had relative macrocephaly and frontal prominence. Whole exome sequencing revealed a de novo c.1225 C>T: p. (R409W) variant in exon 9 of the EEF2 gene (NM_001961.3). Discussion: A comparison of clinical findings suggests that relative macrocephaly/macrocephaly and prominent forehead are consistent and easily identifiable clinical features of EEF2-related neurodevelopmental disorder. The clinical spectrum of this disorder is still emerging. EEF2-related neurodevelopmental disorder should be considered in a child with autism, developmental delays/intellectual disability, macrocephaly/relative macrocephaly, and frontal prominence.

9.
Future Cardiol ; 20(4): 179-182, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-39049772

RESUMO

Hypertrophic cardiomyopathy (HCM) is a well-known manifestation of inherited mitochondrial disease. Still, currently available gene panels do not include mitochondrial genome sequencing. Mitochondrial dysfunction plays a very important role in the pathogenesis of HCM, whether tested positive or negative by the currently available gene panels for HCM. Mitochondrial DNA variations may act as modifiers of disease manifestation in genotype-positive individuals. In genotype-negative individuals, it may be the primary driver of pathogenesis. A recent study has demonstrated that mitochondrial dysfunction is correlated with septal hypertrophy in genotype-negative HCM, which can be amenable to mitochondria-targeted therapy. It is important to consider mitochondrial genome sequencing as part of the genetic evaluation of HCM.


Hypertrophic cardiomyopathy or 'thick heart' is a common heart problem that can lead to abnormal heart rhythm and even heart failure. In older adults, it is often due to high blood pressure that causes the heart to pump against high resistance and hence becoming thick. However, it can occur without high blood pressure, often in young individuals with underlying heart muscle disease. Sometimes, there are many individuals in a family with thick hearts. In these instances, it is likely genetic. The individual may have a faulty gene related to heart muscle function causing the heart to become thick as an adaptation to inefficient heart muscle function. Mitochondria are tiny organelles inside our cells that make energy. When there is mitochondrial damage, heart muscles cannot generate energy efficiently. This can lead to a thick heart as well. Hence, it is important to test mitochondrial genes along with the heart muscle genes to find the cause of thick heart when it is unexplained, or a genetic cause is suspected.


Assuntos
Cardiomiopatia Hipertrófica , DNA Mitocondrial , Humanos , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/diagnóstico , DNA Mitocondrial/genética , Mitocôndrias , Doenças Mitocondriais/genética , Doenças Mitocondriais/diagnóstico , Mutação
11.
DNA Cell Biol ; 40(6): 713-719, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33872068

RESUMO

Coronavirus disease 2019 (COVID-19) is the worst public health crisis of the century. Although we have made tremendous progress in understanding the pathogenesis of this disease, a lot more remains to be learned. Mitochondria appear to be important in COVID-19 pathogenesis because of its role in innate antiviral immunity, as well as inflammation. This article examines pathogenesis of COVID-19 from a mitochondrial perspective and tries to answer some perplexing questions such as why the prognosis is so poor in those with obesity, metabolic syndrome, or type 2 diabetes. Although effective vaccines and antiviral drugs will be the ultimate solution to this crisis, a better understanding of disease mechanisms will open novel avenues for treatment and prevention.


Assuntos
COVID-19/imunologia , Mitocôndrias/imunologia , Pandemias , SARS-CoV-2/imunologia , COVID-19/epidemiologia , Humanos , Imunidade Inata , Inflamação/imunologia , Prognóstico , Tratamento Farmacológico da COVID-19
12.
Artigo em Inglês | MEDLINE | ID: mdl-33437892

RESUMO

Fatty liver disease constitutes a spectrum of liver diseases which begin with simple steatosis and may progress to advance stages of steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The two main etiologies are-alcohol related fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). NAFLD is a global health epidemic strongly associated with modern dietary habits and life-style. It is the second most common cause of chronic liver disease in the US after chronic hepatitis C virus (HCV) infection. Approximately 100 million people are affected with this condition in the US alone. Excessive intakes of calories, saturated fat and refined carbohydrates, and sedentary life style have led to explosion of this health epidemic in developing nations as well. ALD is the third most common cause of chronic liver disease in the US. Even though the predominant trigger for onset of steatosis is different in these two conditions, they share common themes in progression from steatosis to the advance stages. Oxidative stress (OS) is considered a very significant contributor to hepatocyte injury in these conditions. Mitochondrial dysfunction contributes to this OS. Role of mitochondrial dysfunction in pathogenesis of fatty liver diseases is emerging but far from completely understood. A better understanding is essential for more effective preventive and therapeutic interventions. Here, we discuss the pathogenesis and therapeutic approaches of NAFLD and ALD from a mitochondrial perspective.

13.
Eur J Hum Genet ; 29(10): 1566-1569, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33840812

RESUMO

KCNJ16 encodes Kir5.1 and acts in combination with Kir4.1, encoded by KCNJ10, to form an inwardly rectifying K+ channel expressed at the basolateral membrane of epithelial cells in the distal nephron. This Kir4.1/Kir5.1 channel is critical for controlling basolateral membrane potential and K+ recycling, the latter coupled to Na-K-ATPase activity, which determines renal Na+ handling. Previous work has shown that Kcnj16-/- mice and SSKcnj16-/- rats demonstrate hypokalemic, hyperchloremic metabolic acidosis. Here, we present the first report of a patient identified to have biallelic loss-of-function variants in KCNJ16 by whole exome sequencing who presented with chronic metabolic acidosis with exacerbations triggered by minor infections.


Assuntos
Acidose/genética , Hipopotassemia/genética , Mutação com Perda de Função , Canais de Potássio Corretores do Fluxo de Internalização/genética , Acidose/patologia , Alelos , Pré-Escolar , Feminino , Humanos , Hipopotassemia/patologia
14.
J Diabetes Metab Disord ; 19(2): 2017-2022, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33520874

RESUMO

Type 2 diabetes mellitus (T2DM) is global health problem. An estimated 425 million people in the world had diabetes in 2017. It is a major cause of morbidity and mortality worldwide. Although, pathogenesis of T2DM and its complications have been focus of medical research for long, much remains to be learned. A better understanding of molecular pathogenesis is essential for more effective preventive and therapeutic interventions. Role of mitochondria in pathogenesis of metabolic problems such as obesity, metabolic syndrome, and T2DM is the focus of many recent research studies. Mitochondrial dysfunction contributes to the oxidative stress and systemic inflammation leading to insulin resistance (IR). Mitochondria are also essential for pancreatic beta cell insulin secretion. Hence, mitochondria are important players in the pathogenesis of T2DM. In this article, pathogenesis of T2DM is examined from a mitochondrial perspective.

15.
Biochim Biophys Acta Mol Basis Dis ; 1866(10): 165838, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428560

RESUMO

Metabolic syndrome is co-occurrence of obesity, insulin resistance, atherogenic dyslipidemia (high triglyceride, low high density lipoprotein cholesterol), and hypertension. It is a global health problem. An estimated 20%-30% of adults of the world have metabolic syndrome. Metabolic syndrome is associated with increased risk of type 2 diabetes mellitus, nonalcoholic fatty liver disease, myocardial infarction, and stroke. Thus, it is a major cause of morbidity and mortality worldwide. However, molecular pathogenesis of metabolic syndrome is not well known. Recently, there has been interest in the role of mitochondria in pathogenesis of metabolic problems such as obesity, metabolic syndrome, and type 2 diabetes mellitus. Mitochondrial dysfunction contributes to the oxidative stress and systemic inflammation seen in metabolic syndrome. Role of mitochondria in the pathogenesis of metabolic syndrome is intriguing but far from completely understood. However, a better understanding will be very rewarding as it may lead to novel approaches to control this major public health problem. This brief review explores pathogenesis of metabolic syndrome from a mitochondrial perspective.


Assuntos
Síndrome Metabólica/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Humanos , Inflamação/metabolismo , Resistência à Insulina , Síndrome Metabólica/terapia , Doenças Mitocondriais/terapia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Biogênese de Organelas , Estresse Oxidativo , Triglicerídeos/metabolismo
16.
J Transl Genet Genom ; 4: 71-80, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33426504

RESUMO

In eukaryotic cells, mitochondria perform the essential function of producing cellular energy in the form of ATP via the oxidative phosphorylation system. This system is composed of 5 multimeric protein complexes of which 13 protein subunits are encoded by the mitochondrial genome: Complex I (7 subunits), Complex III (1 subunit),Complex IV (3 subunits), and Complex (2 subunits). Effective mitochondrial translation is necessary to produce the protein subunits encoded by the mitochondrial genome (mtDNA). Defects in mitochondrial translation are known to cause a wide variety of clinical disease in humans with high-energy consuming organs generally most prominently affected. Here, we review several classes of disease resulting from defective mitochondrial translation including disorders with mitochondrial tRNA mutations, mitochondrial aminoacyl-tRNA synthetase disorders, mitochondrial rRNA mutations, and mitochondrial ribosomal protein disorders.

17.
Nat Commun ; 11(1): 5797, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-33199684

RESUMO

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.


Assuntos
Proteínas Argonautas/genética , Células Germinativas/metabolismo , Mutação/genética , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/metabolismo , Interferência de RNA , Adolescente , Animais , Proteínas Argonautas/química , Criança , Pré-Escolar , Análise por Conglomerados , Dendritos/metabolismo , Fibroblastos/metabolismo , Inativação Gênica , Células HEK293 , Hipocampo/patologia , Humanos , Camundongos , Simulação de Dinâmica Molecular , Neurônios/metabolismo , Fosforilação , Domínios Proteicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Complexo de Inativação Induzido por RNA/metabolismo , Ratos , Transcriptoma/genética
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