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Endocrine Reviews Mar 2021Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for... (Review)
Review
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
Topics: Adolescent; Animals; Germ-Line Mutation; Humans; Mice; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Quality of Life; Signal Transduction
PubMed: 33249439
DOI: 10.1210/endrev/bnaa031 -
Molecular Psychiatry Dec 2019Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the... (Review)
Review
Depression is a complex disorder that takes an enormous toll on individual health. As affected individuals display a wide variation in their clinical symptoms, the precise neural mechanisms underlying the development of depression remain elusive. Although it is impossible to phenocopy every symptom of human depression in rodents, the preclinical field has had great success in modeling some of the core affective and neurovegetative depressive symptoms, including social withdrawal, anhedonia, and weight loss. Adaptations in select cell populations may underlie these individual depressive symptoms and new tools have expanded our ability to monitor and manipulate specific cell types. This review outlines some of the most recent preclinical discoveries on the molecular and neurophysiological mechanisms in reward circuitry that underlie the expression of behavioral constructs relevant to depressive symptoms.
Topics: Anhedonia; Animals; Depression; Depressive Disorder, Major; Disease Models, Animal; Humans; Motivation; Reward; Social Behavior; Weight Loss
PubMed: 30967681
DOI: 10.1038/s41380-019-0415-3 -
Nature Reviews. Genetics Feb 2023Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous... (Review)
Review
Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.
Topics: Humans; Telomere; Aging; Telomere Homeostasis; Genomic Instability; Biology; Telomerase
PubMed: 36151328
DOI: 10.1038/s41576-022-00527-z -
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 -
Progress in Retinal and Eye Research Nov 2020The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned... (Review)
Review
The ABCA4 protein (then called a "rim protein") was first identified in 1978 in the rims and incisures of rod photoreceptors. The corresponding gene, ABCA4, was cloned in 1997, and variants were identified as the cause of autosomal recessive Stargardt disease (STGD1). Over the next two decades, variation in ABCA4 has been attributed to phenotypes other than the classically defined STGD1 or fundus flavimaculatus, ranging from early onset and fast progressing cone-rod dystrophy and retinitis pigmentosa-like phenotypes to very late onset cases of mostly mild disease sometimes resembling, and confused with, age-related macular degeneration. Similarly, analysis of the ABCA4 locus uncovered a trove of genetic information, including >1200 disease-causing mutations of varying severity, and of all types - missense, nonsense, small deletions/insertions, and splicing affecting variants, of which many are located deep-intronic. Altogether, this has greatly expanded our understanding of complexity not only of the diseases caused by ABCA4 mutations, but of all Mendelian diseases in general. This review provides an in depth assessment of the cumulative knowledge of ABCA4-associated retinopathy - clinical manifestations, genetic complexity, pathophysiology as well as current and proposed therapeutic approaches.
Topics: ATP-Binding Cassette Transporters; DNA; Genetic Therapy; Humans; Mutation; Phenotype; Retinal Diseases
PubMed: 32278709
DOI: 10.1016/j.preteyeres.2020.100861 -
Heart Rhythm Jan 2020In an era of rapid technological development and evolving diagnostic possibilities, the electrocardiogram (ECG) is living an authentic "renaissance" in myocardial... (Review)
Review
In an era of rapid technological development and evolving diagnostic possibilities, the electrocardiogram (ECG) is living an authentic "renaissance" in myocardial diseases. To date, the ECG remains an irreplaceable first step when evaluating patients with hypertrophic cardiomyopathy (HCM) and an abnormal ECG may be the only manifestation of disease at an early stage. In some instances, specific electrical anomalies may differentiate HCM from phenocopies such as cardiac amyloidosis and glycogen storage diseases. The exponential growth in knowledge of the complexity of HCM has led to new challenges in terms of early identification of the disease, differential diagnosis, risk stratification, and development of targeted therapies. In this scenario, the apparently "old fashioned" ECG and the array of ECG-based techniques, ranging from Holter monitoring and loop recorders to exercise testing, are as contemporary as ever. In the present review, we discuss the current role of the ECG in the diagnosis and management of HCM, focusing on various clinical settings where its appropriate use and interpretation can make a difference.
Topics: Cardiomyopathy, Hypertrophic; Disease Management; Electrocardiography; Humans
PubMed: 31349064
DOI: 10.1016/j.hrthm.2019.07.019 -
Nature Cell Biology Aug 2023Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic process starts...
Lipid mobilization through fatty acid β-oxidation is a central process essential for energy production during nutrient shortage. In yeast, this catabolic process starts in the peroxisome from where β-oxidation products enter mitochondria and fuel the tricarboxylic acid cycle. Little is known about the physical and metabolic cooperation between these organelles. Here we found that expression of fatty acid transporters and of the rate-limiting enzyme involved in β-oxidation is decreased in cells expressing a hyperactive mutant of the small GTPase Arf1, leading to an accumulation of fatty acids in lipid droplets. Consequently, mitochondria became fragmented and ATP synthesis decreased. Genetic and pharmacological depletion of fatty acids phenocopied the arf1 mutant mitochondrial phenotype. Although β-oxidation occurs in both mitochondria and peroxisomes in mammals, Arf1's role in fatty acid metabolism is conserved. Together, our results indicate that Arf1 integrates metabolism into energy production by regulating fatty acid storage and utilization, and presumably organelle contact sites.
Topics: Animals; Mitochondria; Peroxisomes; Fatty Acids; Oxidation-Reduction; Lipid Metabolism; Homeostasis; Mammals
PubMed: 37400497
DOI: 10.1038/s41556-023-01180-2 -
The Journal of Allergy and Clinical... Jun 2023Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory... (Review)
Review
Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.
Topics: Humans; Autoimmune Diseases; Immunologic Deficiency Syndromes; Autoimmunity; Common Variable Immunodeficiency
PubMed: 37119983
DOI: 10.1016/j.jaip.2023.04.018 -
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 -
Nature Reviews. Neuroscience May 2021Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of... (Review)
Review
Evidence from human genetic pain disorders shows that voltage-gated sodium channel α-subtypes Nav1.7, Nav1.8 and Nav1.9 are important in the peripheral signalling of pain. Nav1.7 is of particular interest because individuals with Nav1.7 loss-of-function mutations are congenitally insensitive to acute and chronic pain, and there is considerable hope that phenocopying these effects with a pharmacological antagonist will produce a new class of analgesic drug. However, studies in these rare individuals do not reveal how and where voltage-gated sodium channels contribute to pain signalling, which is of critical importance for drug development. More than a decade of research utilizing rodent genetic models and pharmacological tools to study voltage-gated sodium channels in pain has begun to unravel the role of different subtypes. Here, we review the contribution of individual channel subtypes in three key physiological processes necessary for transmission of sensory information to the CNS: transduction of stimuli at peripheral nerve terminals, axonal transmission of action potentials and neurotransmitter release from central terminals. These data suggest that drugs seeking to recapitulate the analgesic effects of loss of function of Nav1.7 will need to be brain-penetrant - which most of those developed to date are not.
Topics: Animals; Humans; NAV1.7 Voltage-Gated Sodium Channel; Pain; Voltage-Gated Sodium Channels
PubMed: 33782571
DOI: 10.1038/s41583-021-00444-w