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Caterina Garone, Juliana Gurgel-Giannetti, Simone Sanna-Cherchi, Sindu Krishna, Ali Naini, Catarina M Quinzii, Michio Hirano
SUCLA2 defects have been associated with mitochondrial DNA (mtDNA) depletion and the triad of hypotonia, dystonia/Leigh-like syndrome, and deafness. A 9-year-old Brazilian boy of consanguineous parents presented with psychomotor delay, deafness, myopathy, ataxia, and chorea. Despite the prominent movement disorder, brain magnetic resonance imaging (MRI) was normal while (1)H-magnetic resonance spectroscopy (MRS) showed lactate peaks in the cerebral cortex and lateral ventricles. Decreased biochemical activities of mitochondrial respiratory chain enzymes containing mtDNA-encoded subunits and mtDNA depletion were observed in muscle and fibroblasts...
September 20, 2016: Journal of Child Neurology
Gergely Kacso, Dora Ravasz, Judit Doczi, Beáta Németh, Ory Madgar, Ann Saada, Polina Ilin, Chaya Miller, Elsebet Ostergaard, Iordan Iordanov, Daniel Adams, Zsuzsanna Vargedo, Masatake Araki, Kimi Araki, Mai Nakahara, Haruka Ito, Aniko Gál, Mária J Molnár, Zsolt Nagy, Attila Patocs, Vera Adam-Vizi, Christos Chinopoulos
Succinate-CoA ligase (SUCL) is a heterodimer enzyme composed of Suclg1 α-subunit and a substrate-specific Sucla2 or Suclg2 β-subunit yielding ATP or GTP, respectively. In humans, the deficiency of this enzyme leads to encephalomyopathy with or without methylmalonyl aciduria, in addition to resulting in mitochondrial DNA depletion. We generated mice lacking either one Sucla2 or Suclg2 allele. Sucla2 heterozygote mice exhibited tissue- and age-dependent decreases in Sucla2 expression associated with decreases in ATP-forming activity, but rebound increases in cardiac Suclg2 expression and GTP-forming activity...
October 15, 2016: Biochemical Journal
Taraka R Donti, Ruchi Masand, Daryl A Scott, William J Craigen, Brett H Graham
Deficiency of the TCA cycle enzyme Succinyl-CoA Synthetase/Ligase (SCS), due to pathogenic variants in subunits encoded by SUCLG1 and SUCLA2, causes mitochondrial encephalomyopathy, methylmalonic acidemia, and mitochondrial DNA (mtDNA) depletion. In this study, we report an 11year old patient who presented with truncal ataxia, chorea, hypotonia, bilateral sensorineural hearing loss and preserved cognition. Whole exome sequencing identified a heterozygous known pathogenic variant and a heterozygous novel missense variant of uncertain clinical significance (VUS) in SUCLG1...
September 2016: Molecular Genetics and Metabolism
Y P Liu, X Y Li, Y Ding, Q Wang, J Q Song, Y Zhang, D X Li, Y P Qin, Y L Yang
OBJECTIVE: To study the clinical and genetic features of the patients with secondary methylmalonic aciduria due to succinate-CoA ligase deficiency. METHOD: From February 2011 to April 2014, 4 Chinese patients with succinate-CoA ligase deficiency and mild methylmalonic aciduria were enrolled in this study. The clinical course, biochemical features, brain MRI findings, and mutations were analyzed. RESULT: Four patients presented with severe psychomotor retardation, hypotonia, seizures, feeding problems and failure to thrive from the age of one day to 6 months...
May 2016: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
May-Britt Tessem, Helena Bertilsson, Anders Angelsen, Tone F Bathen, Finn Drabløs, Morten Beck Rye
Molecular analysis of patient tissue samples is essential to characterize the in vivo variability in human cancers which are not accessible in cell-lines or animal models. This applies particularly to studies of tumor metabolism. The challenge is, however, the complex mixture of various tissue types within each sample, such as benign epithelium, stroma and cancer tissue, which can introduce systematic biases when cancers are compared to normal samples. In this study we apply a simple strategy to remove such biases using sample selections where the average content of stroma tissue is balanced between the sample groups...
2016: PloS One
Olcay Güngör, Ahmet Kağan Özkaya, Gülay Güngör, Kadri Karaer, Cengiz Dilber, Kürşad Aydin
Succinate-CoA ligase, ADP-forming, beta subunit (SUCLA2)-related mitochondrial DNA depletion syndrome is caused by mutations affecting the ADP-using isoform of the beta subunit in succinyl-CoA synthase, which is involved in the Krebs cycle. The SUCLA2 protein is found mostly in heart, skeletal muscle, and brain tissues. SUCLA2 mutations result in a mitochondrial disorder that manifests as deafness, lesions in the basal ganglia, and encephalomyopathy accompanied by dystonia. Such mutations are generally associated with mildly increased plasma methylmalonic acid, increased plasma lactate, elevated plasma carnitine esters, and the presence of methylmalonic acid in urine...
July 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
Soo-Kyung Park, Myunghee Hong, Byong Duk Ye, Kyung-Jo Kim, Sang Hyoung Park, Dong-Hoon Yang, Sung-Wook Hwang, Min Seob Kwak, Ho-Su Lee, Kyuyoung Song, Suk-Kyun Yang
BACKGROUND: The impact of genetic variation in the thiopurine S-methyltransferase (TPMT) gene on thiopurine-induced leukopenia has been well demonstrated. Although xanthine dehydrogenase (XDH) is the second major contributor to azathioprine breakdown, polymorphisms in XDH have rarely been studied in IBD patients. We aim to access association between XDH variants and thiopurine-induced leukopenia by gene-gene interaction in a Crohn's disease (CD) population. STUDY: A total of 964 CD patients treated with thiopurines were recruited from a tertiary referral center...
2016: Scandinavian Journal of Gastroenterology
Rosalba Carrozzo, Daniela Verrigni, Magnhild Rasmussen, Rene de Coo, Hernan Amartino, Marzia Bianchi, Daniela Buhas, Samir Mesli, Karin Naess, Alfred Peter Born, Berit Woldseth, Paolo Prontera, Mustafa Batbayli, Kirstine Ravn, Fróði Joensen, Duccio M Cordelli, Filippo Maria Santorelli, Mar Tulinius, Niklas Darin, Morten Duno, Philippe Jouvencel, Alberto Burlina, Gabriela Stangoni, Enrico Bertini, Isabelle Redonnet-Vernhet, Flemming Wibrand, Carlo Dionisi-Vici, Johanna Uusimaa, Paivi Vieira, Andrés Nascimento Osorio, Robert McFarland, Robert W Taylor, Elisabeth Holme, Elsebet Ostergaard
BACKGROUND: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. PATIENTS AND RESULTS: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations...
March 2016: Journal of Inherited Metabolic Disease
Roeltje R Maas, Adela Della Marina, Arjan P M de Brouwer, Ron A Wevers, Richard J Rodenburg, Saskia B Wortmann
SUCLA2 encodes for a subunit of succinyl-coenzyme A synthase, the enzyme that reversibly synthesises succinyl-coenzyme A and ATP from succinate, coenzyme A and ADP in the Krebs cycle. Disruption of SUCLA2 function can lead to mitochondrial DNA depletion. Patients with a SUCLA2 mutation present with a rare but distinctive deafness-dystonia syndrome. Additionally, they exhibit elevated levels of the characteristic biochemical markers: methylmalonate, C4-dicarboxylic carnitine and lactate are increased in both plasma and urine...
2016: JIMD Reports
Katalin Völgyi, Péter Gulyássy, Krisztina Háden, Viktor Kis, Kata Badics, Katalin Adrienna Kékesi, Attila Simor, Balázs Györffy, Eszter Angéla Tóth, Gert Lubec, Gábor Juhász, Arpád Dobolyi
UNLABELLED: The synapse is a particularly important compartment of neurons. To reveal its molecular characteristics we isolated whole brain synaptic (sMito) and non-synaptic mitochondria (nsMito) from the mouse brain with purity validated by electron microscopy and fluorescence activated cell analysis and sorting. Two-dimensional differential gel electrophoresis and mass spectrometry based proteomics revealed 22 proteins with significantly higher and 34 proteins with significantly lower levels in sMito compared to nsMito...
April 29, 2015: Journal of Proteomics
Zhimei Liu, Fang Fang, Changhong Ding, Husheng Wu, Junlan Lyu, Yun Wu
OBJECTIVE: To analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient, and review the latest clinical research reports. METHOD: Clinical, laboratory and genetic data of one case of SUCLA2-related encephalomyopathic MDS diagnosed by department of Neurology, Beijing Children's Hospital in November, 2013 were reported, and through taking "SUCLA2" as key words to search at CNKI, Wanfang, PubMed and the Human Gene Mutation Database (HGMD) professional to date, the clinical characteristics of 24 reported cases of SUCLA2-related encephalomyopathic MDS in international literature in combination with our case were analyzed...
November 2014: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Arpád Dobolyi, Attila G Bagó, Aniko Gál, Mária J Molnár, Miklós Palkovits, Vera Adam-Vizi, Christos Chinopoulos
We have recently shown that the ATP-forming SUCLA2 subunit of succinyl-CoA ligase, an enzyme of the citric acid cycle, is exclusively expressed in neurons of the human cerebral cortex; GFAP- and S100-positive astroglial cells did not exhibit immunohistoreactivity or in situ hybridization reactivity for either SUCLA2 or the GTP-forming SUCLG2. However, Western blotting of post mortem samples revealed a minor SUCLG2 immunoreactivity. In the present work we sought to identify the cell type(s) harboring SUCLG2 in paraformaldehyde-fixed, free-floating surgical human cortical tissue samples...
April 2015: Journal of Bioenergetics and Biomembranes
Woo-Sung Kwon, Md Saidur Rahman, June-Sub Lee, Jin Kim, Sung-Jae Yoon, Yoo-Jin Park, Young-Ah You, Seongsoo Hwang, Myung-Geol Pang
BACKGROUND: Mammalian spermatozoa must undergo capacitation, before becoming competent for fertilization. Despite its importance, the fundamental molecular mechanisms of capacitation are poorly understood. Therefore, in this study, we applied a proteomic approach for identifying capacitation-related proteins in boar spermatozoa in order to elucidate the events more precisely. 2-DE gels were generated from spermatozoa samples in before- and after-capacitation. To validate the 2-DE results, Western blotting and immunocytochemistry were performed with 2 commercially available antibodies...
2014: BMC Genomics
J P SanGiovanni, R Rosen, S Kaushal
Genome-wide association (GWA) studies apply broad DNA scans on hundreds-of-thousands of common sequence variants in thousands of people for the purpose of mapping trait- or disease-related loci. We provide examples of ligand- and target-based studies from the field of age-related macular degeneration (AMD) to demonstrate the value of the GWA approach in confirmatory and exploratory pharmacogenomics research. Complementing this genomic analysis, we used a simple biochemical retinal pigment epithelium (RPE) oxidative, apoptotic high throughput screening (HTS) assay to identify compounds...
2014: Current Molecular Medicine
Sanna Matilainen, Pirjo Isohanni, Liliya Euro, Tuula Lönnqvist, Helena Pihko, Tero Kivelä, Sakari Knuutila, Anu Suomalainen
Mutations in SUCLA2, encoding the ß-subunit of succinyl-CoA synthetase of Krebs cycle, are one cause of mitochondrial DNA depletion syndrome. Patients have been reported to have severe progressive childhood-onset encephalomyopathy, and methylmalonic aciduria, often leading to death in childhood. We studied two families, with children manifesting with slowly progressive mitochondrial encephalomyopathy, hearing impairment and transient methylmalonic aciduria, without mtDNA depletion. The other family also showed dominant inheritance of bilateral retinoblastoma, which coexisted with mitochondrial encephalomyopathy in one patient...
March 2015: European Journal of Human Genetics: EJHG
Célia Nogueira, Maria Chiara Meschini, Claudia Nesti, Paula Garcia, Luisa Diogo, Carla Valongo, Ricardo Costa, Arnaldo Videira, Laura Vilarinho, Filippo M Santorelli
Succinyl-coenzyme A synthase is a mitochondrial matrix enzyme that catalyzes the reversible synthesis of succinate and adenosine triphosphate (ATP) from succinyl-coenzyme A and adenosine diphosphate (ADP) in the tricarboxylic acid cycle. This enzyme is made up of α and β subunits encoded by SUCLG1 and SUCLA2, respectively. We present a child with severe muscular hypotonia, dystonia, failure to thrive, sensorineural deafness, and dysmorphism. Metabolic investigations disclosed hyperlactacidemia, moderate urinary excretion of methylmalonic acid, and elevated levels of C4-dicarboxylic carnitine in blood...
February 2015: Journal of Child Neurology
Taraka R Donti, Carmen Stromberger, Ming Ge, Karen W Eldin, William J Craigen, Brett H Graham
Mutations in subunits of succinyl-CoA synthetase/ligase (SCS), a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA), and mitochondrial DNA (mtDNA) depletion. A FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES) cells for abnormal mitochondrial phenotypes identified a gene trap allele of Sucla2 (Sucla2(SAβgeo)), which was used to generate transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform of SCS...
February 2014: Disease Models & Mechanisms
Cristiano Rizzo, Sara Boenzi, Rita Inglese, Giancarlo la Marca, Maurizio Muraca, Tegra Barreiro Martinez, David W Johnson, Eleonora Zelli, Carlo Dionisi-Vici
Methylmalonic aciduria (MMA) is one of the most frequent organic acidurias, a class of diseases caused by enzymatic defects mainly involved in the catabolism of branched-chain amino acids. Recently, mild MMA and C4-dicarboxylyl-carnitine (C4DC-C) accumulation have been reported in patients carrying mutation in genes encoding the α-subunit (SUCLG1) and the β-subunit (SUCLA2) of the ADP-forming succinyl-CoA synthetase (SCS). We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify in dried blood spot the two isobaric compounds of C4DC-C, succinyl-carnitine and methylmalonyl-carnitine, to allow the differential diagnosis between classical MMA and SCS-related defects...
February 15, 2014: Clinica Chimica Acta; International Journal of Clinical Chemistry
Arpád Dobolyi, Elsebet Ostergaard, Attila G Bagó, Tamás Dóczi, Miklós Palkovits, Aniko Gál, Mária J Molnár, Vera Adam-Vizi, Christos Chinopoulos
SUCLA2 encodes the ATP-forming β subunit (A-SUCL-β) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-β in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye...
January 2015: Brain Structure & Function
Elham Jaberi, Fereshteh Chitsazian, Gholam Ali Shahidi, Mohammad Rohani, Farzad Sina, Iman Safari, Maryam Malakouti Nejad, Masoud Houshmand, Brandy Klotzle, Elahe Elahi
SUCLA2 is one of several nuclear-encoded genes that can cause encephalomyopathy accompanied by mitochondrial DNA depletion. The disorder usually manifests in early childhood and leads to early death. The gene encodes one of the subunits of succinyl-CoA synthase, the enzyme that catalyzes the reversible conversion of substrates succinyl-CoA and ADP to products succinate and ATP in the tricarboxylic acid pathway. Thirty-two individuals harboring mutations in SUCLA2 have so far been reported, and five different mutations were observed among these individuals...
August 2013: Journal of Human Genetics
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