scholarly journals Studying Lipid-Related Pathophysiology Using the Yeast Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Tyler Ralph-Epps ◽  
Chisom J. Onu ◽  
Linh Vo ◽  
Michael W. Schmidtke ◽  
Anh Le ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Genetic Disorder ◽  
Model System ◽  
Complete Loss ◽  
Barth Syndrome ◽  
Human Diseases ◽  
Model Organisms ◽  
Loss Of Function ◽  
Parkinson’S Diseases ◽  
Yeast Model

Saccharomyces cerevisiae, commonly known as baker’s yeast, is one of the most comprehensively studied model organisms in science. Yeast has been used to study a wide variety of human diseases, and the yeast model system has proved to be an especially amenable tool for the study of lipids and lipid-related pathophysiologies, a topic that has gained considerable attention in recent years. This review focuses on how yeast has contributed to our understanding of the mitochondrial phospholipid cardiolipin (CL) and its role in Barth syndrome (BTHS), a genetic disorder characterized by partial or complete loss of function of the CL remodeling enzyme tafazzin. Defective tafazzin causes perturbation of CL metabolism, resulting in many downstream cellular consequences and clinical pathologies that are discussed herein. The influence of yeast research in the lipid-related pathophysiologies of Alzheimer’s and Parkinson’s diseases is also summarized.

scholarly journals Research on Plants for the Understanding of Diseases of Nuclear and Mitochondrial Origin

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Claudia P. Spampinato ◽  
Diego F. Gomez-Casati
Keyword(s):  
Current Knowledge ◽  
Model System ◽  
Human Diseases ◽  
Model Organisms ◽  
Human Cell Lines ◽  
Molecular Defects ◽  
Human Genes ◽  
Clinical Disorders ◽  
Mitochondrial Origin ◽  
Experimental Findings

Different model organisms, such asEscherichia coli,Saccharomyces cerevisiae,Caenorhabditis elegans,Drosophila melanogaster, mouse, cultured human cell lines, among others, were used to study the mechanisms of several human diseases. Since human genes and proteins have been structurally and functionally conserved in plant organisms, the use of plants, especiallyArabidopsis thaliana, as a model system to relate molecular defects to clinical disorders has recently increased. Here, we briefly review our current knowledge of human diseases of nuclear and mitochondrial origin and summarize the experimental findings of plant homologs implicated in each process.

scholarly journals Barth syndrome mutations that cause tafazzin complex lability

2011 ◽  
Vol 192 (3) ◽  
pp. 447-462 ◽  
Author(s):  
Steven M. Claypool ◽  
Kevin Whited ◽  
Santi Srijumnong ◽  
Xianlin Han ◽  
Carla M. Koehler
Keyword(s):  
Mitochondrial Function ◽  
Protein Complexes ◽  
Barth Syndrome ◽  
Human Diseases ◽  
Intermembrane Space ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Low Levels ◽  
Tafazzin Gene ◽  
Mutant Polypeptides

Deficits in mitochondrial function result in many human diseases. The X-linked disease Barth syndrome (BTHS) is caused by mutations in the tafazzin gene TAZ1. Its product, Taz1p, participates in the metabolism of cardiolipin, the signature phospholipid of mitochondria. In this paper, a yeast BTHS mutant tafazzin panel is established, and 18 of the 21 tested BTHS missense mutations cannot functionally replace endogenous tafazzin. Four BTHS mutant tafazzins expressed at low levels are degraded by the intermembrane space AAA (i-AAA) protease, suggesting misfolding of the mutant polypeptides. Paradoxically, each of these mutant tafazzins assembles in normal protein complexes. Furthermore, in the absence of the i-AAA protease, increased expression and assembly of two of the BTHS mutants improve their function. However, the BTHS mutant complexes are extremely unstable and accumulate as insoluble aggregates when disassembled in the absence of the i-AAA protease. Thus, the loss of function for these BTHS mutants results from the inherent instability of the mutant tafazzin complexes.

scholarly journals A new murine model of Barth Syndrome neutropenia links TAFAZZIN deficiency to increased ER stress induced apoptosis

2022 ◽  
Author(s):  
Jihee Sohn ◽  
Jelena Milosevic ◽  
Thomas Brouse ◽  
Najihah Aziz ◽  
Jenna Elkhoury ◽  
...  
Keyword(s):  
Er Stress ◽  
Murine Model ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Model System ◽  
Barth Syndrome ◽  
Loss Of Function ◽  
Inner Mitochondrial Membrane ◽  
Hematopoietic Stem ◽  
Increased Sensitivity

Barth syndrome is an inherited X-linked disorder that leads to cardiomyopathy, skeletal myopathy and neutropenia. These symptoms result from the loss of function of the enzyme TAFAZZIN, a transacylase located in the inner mitochondrial membrane that is responsible for the final steps of cardiolipin production. The link between defective cardiolipin maturation and neutropenia remains unclear. To address potential mechanisms of neutropenia, we examined myeloid progenitor development within the fetal liver of TAFAZZIN knock-out animals as well as within the adult bone marrow of wild-type recipients transplanted with TAFAZZIN KO hematopoietic stem cells. We also used the ER Hoxb8 system of conditional immortalization to establish a new murine model system for the ex vivo study of TAFAZZIN-deficient neutrophils. The TAFAZZIN KO cells demonstrated the expected dramatic differences in cardiolipin maturation that result from a lack of TAFAZZIN enzyme activity. Contrary to our hypothesis, we did not identify any significant differences in neutrophil development or neutrophil function across a variety of assays including phagocytosis, and the production of cytokines or reactive oxygen species. However, transcriptomic analysis of the TAFAZZIN-deficient neutrophil progenitors demonstrated an upregulation of markers of endoplasmic reticulum stress and confirmatory testing demonstrated that the TAFAZZIN-deficient cells had increased sensitivity to certain ER stress mediated and non ER stress mediated triggers of apoptosis. While the link between increased sensitivity to apoptosis and the variably penetrant neutropenia phenotype seen in some Barth syndrome patients remains to be clarified, our studies and new model system set a foundation for further investigation.

Deficiency in mitochondrial anionic phospholipid synthesis impairs cell wall biogenesis

2005 ◽  
Vol 33 (5) ◽  
pp. 1158-1161 ◽  
Author(s):  
Q. Zhong ◽  
M.L. Greenberg
Keyword(s):  
Cell Wall ◽  
Elevated Temperatures ◽  
Genetic Disorder ◽  
Barth Syndrome ◽  
Loss Of Function ◽  
Anionic Phospholipid ◽  
Anionic Phospholipids ◽  
Growth Defects ◽  
Cell Wall Biogenesis ◽  
Severe Growth

Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1, which encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial anionic phospholipids phosphatidylglycerol and CL. The pgs1Δ mutant exhibits severe growth defects at 37°C. To understand the essential functions of mitochondrial anionic lipids at elevated temperatures, we isolated suppressors of pgs1Δ that grew at 37°C. The present review summarizes our analysis of suppression of pgs1Δ growth defects by a mutant that has a loss-of-function mutation in KRE5, a gene involved in cell wall biogenesis.

Hypoactivity, Abnormal Musculature, and Learning and Memory Defects in slc6a3 zebrafish Mutant Larvae

2021 ◽  
Author(s):  
Yu Jiang ◽  
Nan Geng ◽  
Peisong Wang ◽  
Xiaojie Lu
Keyword(s):  
Learning And Memory ◽  
High Throughput Screening ◽  
Critical Role ◽  
Model Organism ◽  
Dopamine Metabolism ◽  
Complete Loss ◽  
Model Organisms ◽  
Suitable Model ◽  
Loss Of Function ◽  
Dopamine Signaling

Abstract Dopamine (DA) is one of the most common neurotransmitters in living organisms and is involved in the regulation of behavior, physiology, and disease. The dopamine transporter (DAT, encoded by the slc6a3 gene) re-uptakes dopamine from the synaptic cleft back into neurons, which plays a critical role in regulating dopamine signaling. Clinically, mutations in slc6a3 have been implicated in various diseases. Zebrafish are good model organisms for studying the functions of slc6a3 and dopamine. Work using the zebrafish slc6a3 mutant has previously been reported, but this mutant is not a complete loss-of-function mutant. In the present study, we knocked out the slc6a3 gene using CRISRP/Cas9 technology and obtained a zebrafish mutant with complete loss of function of slc6a3. Behavioral assessments and quantitative reverse transcription (qRT)-PCR revealed musculature injury, decreased activity, and decreased learning and memory ability in the slc6a3 mutant. This study provides a new theoretical basis for understanding the function of slc6a3 and provides a new model organism for studying the molecular pathology underscoring dopamine metabolism-related diseases. It also provides a suitable model for high-throughput screening of small-molecule drugs targeting slc6a3.

scholarly journals Mutational analysis of capping protein function in Saccharomyces cerevisiae.

1996 ◽  
Vol 7 (1) ◽  
pp. 1-15 ◽  
Author(s):  
G I Sizonenko ◽  
T S Karpova ◽  
D J Gattermeir ◽  
J A Cooper
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Actin Filaments ◽  
Mutational Analysis ◽  
Biochemical Property ◽  
Complete Loss ◽  
Loss Of Function ◽  
Capping Protein ◽  
Actin Cables

To investigate physiologic functions and structural correlates for actin capping protein (CP), we analyzed site-directed mutations in CAP1 and CAP2, which encode the alpha and beta subunits of CP in Saccharomyces cerevisiae. Mutations in four different regions caused a loss of CP function in vivo despite the presence of mutant protein in the cells. Mutations in three regions caused a complete loss of all aspects of function, including the actin distribution, viability with sac6, and localization of CP to actin cortical patches. Mutation of the fourth region led to partial loss of only one function-formation of actin cables. Some mutations retained function and exhibited the complete wild-type phenotype, and some mutations led to a complete loss of protein and therefore loss of function. The simplest hypothesis that can explain these results is that a single biochemical property is necessary for all in vivo functions. This biochemical property is most likely binding to actin filaments, because the nonfunctional mutant CPs no longer co-localize with actin filaments in vivo and because direct binding of CP to actin filaments has been well established by studies with purified proteins in vitro. More complex hypotheses, involving the existence of additional biochemical properties important for function, cannot be excluded by this analysis.

Chronic Ischemic Monomelic Neuropathy after Arteriovenous Fistula Creation: A Unique Presentation of Vascular Steal

2020 ◽  
Vol 3 (2) ◽  
pp. 147-150
Author(s):  
Kaczynski RE ◽  
Asaad Y ◽  
Valentin-Capeles N ◽  
Battista J
Keyword(s):  
Arteriovenous Fistula ◽  
Complete Loss ◽  
Dialysis Access ◽  
Loss Of Function ◽  
Access Site ◽  
Surgical Ligation ◽  
Arteriovenous Access ◽  
Vascular Steal ◽  
Steal Syndrome

We discuss a case of a 58 year old male who presented for left upper extremity steal syndrome including ischemic monomelic neuropathy (IMN) 1.5 months after arteriovenous fistula creation. He presented after three surgical attempts to salvage his fistula with rest pain, complete loss of function with contracture of the 4th and 5th digits, and loss of sensation in the ulnar distribution for more than three weeks. At our institution, he underwent surgical ligation of the distal fistula and creation of a new fistula proximally, resulting in complete resolution of his vascular steal symptoms almost immediately despite the chronicity prior to surgical presentation. Our patient provides a unique perspective regarding dialysis access salvage versus patient quality of life. The patients’ functional status and pain levels should take precedence over salvage of an arteriovenous access site, and early ligation of the access should be completed prior to chronic IMN development. However, if a patient presents late along the IMN course, we recommend strong consideration of access ligation in order to attempt to regain the full neurovascular function of the extremity as we experienced in our patient.

scholarly journals Inborn errors of immunity—recent advances in research on the pathogenesis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Motoi Yamashita ◽  
Kento Inoue ◽  
Tsubasa Okano ◽  
Tomohiro Morio
Keyword(s):  
Immune System ◽  
Hematopoietic Cell Transplantation ◽  
Epigenetic Modification ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Whole Genome Analysis ◽  
Curative Therapy ◽  
Inborn Errors Of Immunity ◽  
Recent Advances

AbstractPrimary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.

scholarly journals Development and content validity of the Barth Syndrome Symptom Assessment (BTHS-SA) for adolescents and adults

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Chad Gwaltney ◽  
Jonathan Stokes ◽  
Anthony Aiudi ◽  
Iyar Mazar ◽  
Sarah Ollis ◽  
...  
Keyword(s):  
Clinical Studies ◽  
Genetic Disorder ◽  
Signs And Symptoms ◽  
Symptom Assessment ◽  
Barth Syndrome ◽  
Therapeutic Area ◽  
Symptom Experience ◽  
Patient Reported ◽  
Adolescents And Adults ◽  
Syndrome Symptom

Abstract Background Barth Syndrome (BTHS) is a rare genetic disorder that presents as a complex of debilitating symptoms and reduced life expectancy. Well-developed, BTHS-specific assessments measuring primary signs and symptoms of BTHS are not currently available, making it difficult to evaluate treatment effects in BTHS clinical studies. The objective of this research was to develop symptom-focused patient-reported outcome (PRO) measures for use in clinical studies with adolescents and adults with BTHS. Methods Concept elicitation interviews (CEIs) with pediatric (n = 18, age < 16 years) and adult (n = 15, age ≥ 16 years) individuals with BTHS and/or their caregivers were conducted to identify signs and symptoms relevant to BTHS and important to individuals with the condition. Based on CEI results, questionnaire construction activities were conducted to create unique adolescent and adult versions of the Barth Syndrome-Symptom Assessment (BTHS-SA). The questionnaires were evaluated in cognitive debriefing interviews (CDIs) with adolescents (n = 12; age 12- < 16 years) and adults (n = 12; age ≥ 16 years) with BTHS to assess relevance and readability of the tools. Results During the CEIs, a total of 48 and 40 signs and symptoms were reported by the pediatric and adult groups, respectively; 31 were reported by both age groups. Fatigue/tiredness and muscle weakness were the symptoms most frequently reported by both pediatric and adult patients with BTHS as important to improve with an effective treatment. The CEI results informed construction of a nine-item version of the BTHS-SA for adolescents and an eight-item version for adults. Developed for daily administration, each version asks respondents to rate symptom severity “at its worst” over the 24 h prior to administration. CDIs with both adolescents and adults with BTHS demonstrated that each BTHS-SA version was reflective of the disease experience and that respondents could interpret the questionnaire as intended and provide responses that accurately reflected their symptom experience. Conclusions The BTHS-SA adolescent and adult versions are content-valid PRO measures that can be used to evaluate severity of disease-specific symptoms in future clinical trials. Given the lack of available and well-developed assessments in this underserved therapeutic area, these tools fulfill a need for clinical researchers developing treatments for individuals with BTHS.

scholarly journals Responsiveness to exogenous cAMP of a Saccharomyces cerevisiae strain conferred by naturally occurring alleles of PDE1 and PDE2.

Genetics ◽  
1993 ◽  
Vol 135 (2) ◽  
pp. 321-326 ◽  
Author(s):  
H Mitsuzawa
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Slow Growth ◽  
Loss Of Function ◽  
Wild Type ◽  
Triple Mutant ◽  
Apparent Absence ◽  
Camp Pathway ◽  
Naturally Occurring ◽  
Elevated Activity ◽  
Growth Phenotype

Abstract The Saccharomyces cerevisiae strain P-28-24C, from which cAMP requiring mutants derived, responded to exogenously added cAMP. Upon the addition of cAMP, this strain showed phenotypes shared by mutants with elevated activity of the cAMP pathway. Genetic analysis involving serial crosses of this strain to a strain with another genetic background revealed that the responsiveness to cAMP results from naturally occurring loss-of-function alleles of PDE1 and PDE2, which encode low and high affinity cAMP phosphodiesterases, respectively. In addition, P-28-24C was found to carry a mutation conferring slow growth that lies in CYR1, which encodes adenylate cyclase, and the slow growth phenotype caused by the cyr1 mutation was suppressed by the pde2 mutation. Therefore P-28-24C is fortuitously a pde1 pde2 cyr1 triple mutant. Responsiveness to cAMP conferred by pde mutations suggests that S. cerevisiae cells are permeable to cAMP to some extent and that the apparent absence of effect of exogenously added cAMP on wild-type cells is due to immediate degradation by cAMP phosphodiesterases.

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