DOCSLIB.ORG

A Novel Mutation in the AGXT Gene Causing Primary Hyperoxaluria Type I: Genotype–Phenotype Correlation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Mutation in the AGXT Gene Causing Primary Hyperoxaluria Type I: Genotype–Phenotype Correlation c Indian Academy of Sciences RESEARCH ARTICLE A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype–phenotype correlation SAOUSSEN M’DIMEGH1∗, CÉCILE AQUAVIVA-BOURDAIN2, ASMA OMEZZINE1, IBTIHEL M’BAREK1, GENEVIÉVE SOUCHE2, DORSAF ZELLAMA4, KAMEL ABIDI3, ABDELATTIF ACHOUR4, TAHAR GARGAH3, SAOUSSEN ABROUG3 and ALI BOUSLAMA1 1Biochemistry Department, LR12SP11, Sahloul University Hospital, 4054 Sousse, Tunisia 2Laboratory of Inborn Metabolic Diseases, Centre de Biologie Est, Hospices Civils de Lyon, Lyon, 69677 Bron Cedex, France 3Pediatric Department, Charles Nicolle University Hospital, 1002-2 Tunis, Tunisia 4Nephrology Department, Sahloul University Hospital, 4054 Sousse, Tunisia Abstract Primary hyperoxaluria type I (PH1) is an autosomal recessive metabolic disorder caused by inherited mutations in the AGXT gene encoding liver peroxisomal alanine : glyoxylate aminotransferase (AGT) which is deficient or mistargeted to mitochon- dria. PH1 shows considerable phenotypic and genotypic heterogeneity. The incidence and severity of PH1 varies in different geographic regions. DNA samples of the affected members from two unrelated Tunisian families were tested by amplifying and sequencing each of the AGXT exons and intron–exon junctions. We identified a novel frameshift mutation in the AGXT gene, the c.406_410dupACTGC resulting in a truncated protein (p.Gln137Hisfs*19). It is found in homozygous state in two nonconsanguineous unrelated families from Tunisia. These molecular findings provide genotype/phenotype correlations in the intrafamilial phenotypic and permit accurate carrier detection, and prenatal diagnosis. The novel p.Gln137Hisfs*19 mutation detected in our study extend the spectrum of known AGXT gene mutations in Tunisia. [M’Dimegh S., Aquaviva-Bourdain C., Omezzine A., M’Barek I., Souche G., Zellama D., Abidi K., Achour A., Gargah T., Abroug S. and Bouslama A. 2016 A novel mutation in the AGXT gene causing primary hyperoxaluria type I: genotype–phenotype correlation. J. Genet. 95, 659–666] Introduction Most of the PH1-causing mutations identified on the AGXT gene are single base pair substitutions leading to the Primary hyperoxaluria type1 (PH1) is an autosomal reces- synthesis of an aberrant gene product (Williams et al. 2009). sive metabolic disorder caused by inherited mutations in the Wild-type AGXT gene comes in two polymorphic variants, AGXT gene encoding liver peroxisomal alanine : glyoxylate the most frequent major haplotype (Maj) and the less fre- aminotransferase (AGT) (Danpure and Jennings 1986). AGT quent minor haplotype (Min), carrying two single amino acid is a pyridoxal5 -phosphate (PLP)-dependent enzyme that cat- substitutions (p.Pro11Leu and p.Ile340Met) among other alyzes the transamination between L-alanine and glyoxylate genomic changes in strong linkage disequilibrium. This fact to pyruvate and glycine, respectively. The absence of func- can help in the clinic, when searching for mutations in new tional AGT leads to glyoxylate accumulation peroxisomes. PH1 cases (Williams and Rumsby 2007). The Min haplo- Glyoxylate is then transported into the hepatocyte cytosol to type (p.Pro11Leu) allows a small portion of AGT (about be oxidized to oxalate by cytosolic L-lactate dehydrogenase. 5%) to be rerouted from peroxisomes to mitochondria (Lumb Oxalate overproduction leads to the formation and deposition and Danpure 2000). The p.Pro11Leu does not cause PH1 by of insoluble calcium oxalate crystals, expand in nephrocal- itself, but it is known to act synergistically with the delete- cinosis and urolithiasis. This ultimately causes renal failure rious effects of several common mutations that leads to sen- and the consequent systemic oxalosis with calcium oxalate sitization of the protein (Santana et al. 2003; Danpure and precipitation in the whole body (Hoppe et al. 2009). Rumsby 2004). Most of the mutations described are typi- cally found in either Maj or Min haplotypes, but rarely in ∗ For correspondence. E-mail: [email protected]. both (Williams and Rumsby 2007). AGXT mutations result in Keywords. primary hyperoxaluria type 1; AGXT gene; genotype–phenotype correlations. Journal of Genetics, DOI 10.1007/s12041-016-0676-4, Vol. 95, No. 3, September 2016 659 Saoussen M’Dimegh et al. different phenotypic expressions of the disease due to various Methods molecular mechanisms. Four basic mechanisms have been reported to explain the consequences of mutations: mito- Mutational analysis chondrial mistargeting, protein aggregation, abolition of cat- Genomic DNA was extracted from peripheral blood leuco- alytic activity (catalytic defects) and synthesis defect (Salido cytes. Initially, the seven most frequent mutations (c.33dupC et al. 2012). (p.Lys12GlnfsX156), c.508G>A (p.G170R), c.731T>C In the present study, we describe a novel mutation in AGXT (p.I244T), c.454T>A (p.F152I), c.322T>C (p.W108R), identified in two unrelated Tunisian PH1 families. We have c.976delG (p.Val326fs) and c.588G>A (p.G156R)) were also analysed the clinical features to investigate a possible tested by amplification of genomic DNA and restriction relationship between genotype and phenotype. enzyme digestion using primers and conditions that were pre- viously documented (Purdue et al. 1990; Rinat et al. 1999; Coulter-Mackie et al. 2005). The PCR test designed to detect Materials and methods c.33dupC mutation was used simultaneously to distinguish Subjects and data collection the Maj and Min alleles by the research of the IVS1+74 bp in intron 1, which is a characteristic duplication for the Min PH1 was diagnosed in two patients from two unrelated haplotype (Coulter-Mackie et al. 2005). Tunisian families. Informed consent was obtained from all Next, the 11 exons and exon–intron boundaries of the patients for the collection of blood samples. Familial screen- AGXT gene were amplified from genomic DNA using stan- ing in family 2 revealed another affected patient. dard PCR procedures. Direct sequencing of purified PCR products was performed using the BigDye Terminator v3.1 Family 1: Patient II-5, a 8-year-old boy who was diagnosed sequencing kit (Applied Biosystems, Foster City, USA) and with nephrolithiasis at the age of 5, and had been maintained an ABI 3730 genetic analyser. The sequencing of all 11 on dialysis therapy for 7 years prior to the study. exons and flanking intronic sequences of the AGXT gene was performed at the reference laboratory in Lyon, France. Family 2: Other samples were obtained from members of Sequences were analysed using Seqscape Analysis Soft- another family, including a 20-year-old girl (patient V-3) and ware (Applied Biosystems) in comparison with GenBank a 9-year-old boy (patient V-6), who were the case index and reference genomic sequence (NM 000030.2). were diagnosed with nephrolithiasis and her sister (patient Assessment of pathogenicity V-4), 16 years old, who was found by family screening. The families pedigree are shown in figure 1. To investigate the pathogenicity of variants, we performed An information sheet was prepared including the follow- in silico analysis using the AlamutR software (Interactive ing data: clinical presentation, biochemical and radiological Biosoftware, member of the Human Genome Variation data, treatment and outcomes. Society and EBI SME Support Forum). Figure 1. Pedigree of the families under study. 660 Journal of Genetics, Vol. 95, No. 3, September 2016 Novel mutation in the AGXT gene and outcome Biochemical analysis recurrent kidney stones. She had a family history of renal failure (patient III-1), but not tested for PH1, which would The urinary oxalate excretion was assayed by a colorimet- be most likely affected by PH1. Physical examination was ric enzymatic method in 24-h urine collections. The plasma normal. Laboratory studies showed: urea = 6.8 mmol/L, cre- oxalate levels were measured by HPLC method in a spe- atinine = 133 μmol/L, Na = 135 mmol/L, K = 5 mmol/L, cialized French laboratory of clinical pathology. In children, Ca = 2.17 mmol/L, Hb = 11.7g/dL, CBEU was positive of the renal function was estimated by the Schwartz formula Enteroccus faecalis germ. Renal ultrasound showed a nor- (Schwartz et al. 1987). mal sized kidneys and multiple bilateral lithiasis. She was Equations of Schwartz: eGFR (glomerular filtration rate) treated with high fluid intake, strict dietary restrictions on 2 = k × height (cm) oxalate-containing foods and a trial of pyridoxine for many (mL/min/1.73 m ) serum creatinine (mg/dL) (the considered k values were 0.55 for girls and for boys <12). months. Then, she had a rise in the creatinine concentration i.e. 172 μmol/L. Patient V-6, a 9-year-old boy was admitted to hospital to manage familial nephropathy. He is sibling of patient V-3. Results He presented with diagnosis of urolithiasis and nephrocalci- nosis. In his past history, he had repeated episodes of kidney Clinical report stone and urinary tract infection of Proteus and Entero- Family 1: Patient II-5 is an 8 years boy, native to central bacter germs at the age of 4 years. He had been receiving western Tunisia. He was apparently healthy until 5 years of an ureterostomy with stone extraction, several ureteroscopy age when he was admitted with symptoms of a urinary tract with fragmentation of calculi and a lithotripsy. Stone anal- infection. In his past history, he had a recurrent urinary tract ysis showed whewellite. Physical examination was normal. infection. At the time of admission, the child appeared critically Laboratory studies showed: clearance = 72 mL/min per ill with generalized oedema and pallor. Blood pressure 1.73 m2,urea= 7.1 mmol/L, creatinine = 84 μmol/L, Na = was elevated. Renal ultrasonography revealed multiple bilat- 136 mmol/L, K = 3.7 mmol/L, Ca = 2.41 mmol/L, Hb = eral nephrocalcinosis and urolithiasis with the suspicion 9.3 g/dL, CBEU was positive. Renal ultrasound showed an of PH1. The level of 24-h urinary oxalate excretion was asymmetric size of kidneys and bilateral medullary nephro- very high (1828 mmol/L), oxalate : creatinine ratio was calcinosis. Urinary oxalate excretion was 0.02 mmol/24 h 0.712 mmol/mmol (normal value 0.085 at 10 years of age) which is normal and (normal 0.14–0.42 mmol/24 h).
Load more

Recommended publications
  • CDH12 Cadherin 12, Type 2 N-Cadherin 2 RPL5 Ribosomal
    5 6 6 5 . 4 2 1 1 1 2 4 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 A A A A A A A A A A A A A A A A A A A A C C C C C C C C C C C C C C C C C C C C R R R R R R R R R R R R R R R R R R R R B , B B B B B B B B B B B B B B B B B B B , 9 , , , , 4 , , 3 0 , , , , , , , , 6 2 , , 5 , 0 8 6 4 , 7 5 7 0 2 8 9 1 3 3 3 1 1 7 5 0 4 1 4 0 7 1 0 2 0 6 7 8 0 2 5 7 8 0 3 8 5 4 9 0 1 0 8 8 3 5 6 7 4 7 9 5 2 1 1 8 2 2 1 7 9 6 2 1 7 1 1 0 4 5 3 5 8 9 1 0 0 4 2 5 0 8 1 4 1 6 9 0 0 6 3 6 9 1 0 9 0 3 8 1 3 5 6 3 6 0 4 2 6 1 0 1 2 1 9 9 7 9 5 7 1 5 8 9 8 8 2 1 9 9 1 1 1 9 6 9 8 9 7 8 4 5 8 8 6 4 8 1 1 2 8 6 2 7 9 8 3 5 4 3 2 1 7 9 5 3 1 3 2 1 2 9 5 1 1 1 1 1 1 5 9 5 3 2 6 3 4 1 3 1 1 4 1 4 1 7 1 3 4 3 2 7 6 4 2 7 2 1 2 1 5 1 6 3 5 6 1 3 6 4 7 1 6 5 1 1 4 1 6 1 7 6 4 7 e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l l p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m
    [Show full text]
  • Supplementary Materials
    Supplementary Materials COMPARATIVE ANALYSIS OF THE TRANSCRIPTOME, PROTEOME AND miRNA PROFILE OF KUPFFER CELLS AND MONOCYTES Andrey Elchaninov1,3*, Anastasiya Lokhonina1,3, Maria Nikitina2, Polina Vishnyakova1,3, Andrey Makarov1, Irina Arutyunyan1, Anastasiya Poltavets1, Evgeniya Kananykhina2, Sergey Kovalchuk4, Evgeny Karpulevich5,6, Galina Bolshakova2, Gennady Sukhikh1, Timur Fatkhudinov2,3 1 Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia 2 Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, Moscow, Russia 3 Histology Department, Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia 4 Laboratory of Bioinformatic methods for Combinatorial Chemistry and Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia 5 Information Systems Department, Ivannikov Institute for System Programming of the Russian Academy of Sciences, Moscow, Russia 6 Genome Engineering Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia Figure S1. Flow cytometry analysis of unsorted blood sample. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S2. Flow cytometry analysis of unsorted liver stromal cells. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S3. MiRNAs expression analysis in monocytes and Kupffer cells. Full-length of heatmaps are presented.
    [Show full text]
  • AMPK Signaling Regulates Expression of Urea Cycle Enzymes in Response to Changes in Dietary Protein Intake
    bioRxiv preprint doi: https://doi.org/10.1101/439380; this version posted October 10, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. AMPK signaling regulates expression of urea cycle enzymes in response to changes in dietary protein intake Sandra Kirsch Heibel1Y, Peter J McGuire2Y, Nantaporn Haskins1, Himani Datta Majumdar1, Sree Rayavarapu1‡, Kanneboyina Nagaraju3, Yetrib Hathout3, Kristy Brown1, Mendel Tuchman1, Ljubica Caldovic1*, 1 Center for Genetic Medicine Research/Children's National Medical Center, Washington, DC, USA 2 National Human Genome Research Institute/National Institutes for Health, Bethesda, MD, USA 3 Department of Pharmaceutical Sciences/Binghamton University, Binghamton NY, USA YThese authors contributed equally to this work. ‡Current address: Division of Clinical Review, Office of Bioequivalence, Office of Generic Drugs, Center for Drug Evaluation and Research/Food and Drug Administration, Silver Spring, MD, USA * [email protected] Abstract Abundance of urea cycle enzymes in the liver is regulated by the dietary protein intake. Although urea cycle enzyme levels rise in response to a high protein diet, signaling networks that sense dietary protein intake and trigger changes in expression of urea cycle genes have not been identified. The aim of this study was to identify signaling pathway(s) that respond to changes in protein intake and regulate expression of urea cycle genes in mice and human hepatocytes. Mice were adapted to either control or high (HP) protein diets followed by isolation of liver protein and mRNA and integrated analysis of the proteomic and transcriptome profiles.
    [Show full text]
  • AGXT Gene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria
    J Am Soc Nephrol 12: 2072–2079, 2001 AGXT Gene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria ANTONIO AMOROSO,*† DOROTI PIRULLI,* FIORELLA FLORIAN,‡ DANIELA PUZZER,† MICHELE BONIOTTO,* SERGIO CROVELLA,* SILVIA ZEZLINA,† ANDREA SPANO` ,† GINA MAZZOLA,§ SILVANA SAVOLDI,࿣ CRISTINA FERRETTINI,¶ SILVIA BERUTTI,¶ MICHELE PETRARULO,¶ and MARTINO MARANGELLA¶ *Section of Genetics, Department of Reproductive and Developmental Science, University of Trieste, Trieste, Italy; †Medical Genetics Service, IRCCS Burlo Garofolo, Trieste, Italy; ‡Department of Biology, University of Trieste, Trieste, Italy; §Transplant Immunology Service, Ospedale S. Giovanni Battista di Torino, Torino, Italy; ࿣Division of Nephrology and Dialysis, Azienda Ospedaliera Triestina, Trieste, Italy; and ¶Renal Stones Center, Ospedale Mauriziano Umberto I, Torino, Italy. Abstract. Primary hyperoxaluria type 1 (PH1) is an autosomal were performed. Both mutant alleles were found in 21 out of recessive disorder that is caused by a deficiency of alanine: 23 patients, and 13 different mutations were recognized in glyoxylate aminotransferase (AGT), which is encoded by a exons 1, 2, 4, and 10. Normalized AGT activity was lower in single copy gene (AGXT). Molecular diagnosis was used in the severe form than in the adult form (P Ͻ 0.05). Double conjunction with clinical, biochemical, and enzymological data heterozygous patients presented a lower age at the onset of the to evaluate genotype-phenotype correlation. Twenty-three un- disease (P ϭ 0.025), and they were more frequent in group A related, Italian PH1 patients were studied, 20 of which were (75%) than in the group B (14%; P ϭ 0.0406). The T444C grouped according to severe form of PH1 (group A), adult mutation was more frequent in the severe form (P Ͻ 0.05), and form (group B), and mild to moderate decrease in renal func- the opposite was observed for G630A (P Ͻ 0.05).
    [Show full text]
  • Primary Hyperoxaluria Type 1: AGT Mistargeting Highlights the Fundamental Differences Between the Peroxisomal and Mitochondrial Protein Import Pathways
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1763 (2006) 1776–1784 www.elsevier.com/locate/bbamcr Review Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways Christopher J. Danpure Department of Biology, University College London, Gower Street, London WC1E 6BT, UK Received 28 April 2006; received in revised form 1 August 2006; accepted 18 August 2006 Available online 24 August 2006 Abstract Primary hyperoxaluria type 1 (PH1) is an atypical peroxisomal disorder, as befits a deficiency of alanine:glyoxylate aminotransferase (AGT), which is itself an atypical peroxisomal enzyme. PH1 is characterized by excessive synthesis and excretion of the metabolic end-product oxalate and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract. Disease in many patients is caused by a unique protein trafficking defect in which AGT is mistargeted from peroxisomes to mitochondria, where it is metabolically ineffectual, despite remaining catalytically active. Although the peroxisomal import of human AGT is dependent upon the PTS1 import receptor PEX5p, its PTS1 is exquisitely specific for mammalian AGT, suggesting the presence of additional peroxisomal targeting information elsewhere in the AGT molecule. This and many other functional peculiarities of AGT are probably a consequence of its rather chequered evolutionary history, during which much of its time has been spent being a mitochondrial, rather than a peroxisomal, enzyme. Analysis of the molecular basis of AGT mistargeting in PH1 has thrown into sharp relief some of the fundamental differences between the requirements of the peroxisomal and mitochondrial protein import pathways, particularly the properties of peroxisomal and mitochondrial matrix targeting sequences and the different conformational limitations placed upon importable cargos.
    [Show full text]
  • Phyre 2 Results for P50277
    Email [email protected] Description P50277 Mon Jul 2 19:25:55 BST Date 2012 Unique Job 2972c4295ed43821 ID Detailed template information # Template Alignment Coverage 3D Model Confidence % i.d. Template Information PDB header:transferase Chain: B: PDB Molecule:adenosylmethionine-8-amino-7- 1 c4a0rB_ Alignment 100.0 23 oxononanoate PDBTitle: structure of bifunctional dapa aminotransferase-dtb synthetase from2 arabidopsis thaliana bound to dethiobiotin (dtb). PDB header:transferase Chain: A: PDB Molecule:aminotransferase, class iii; 2 c3hmuA_ 100.0 27 Alignment PDBTitle: crystal structure of a class iii aminotransferase from2 silicibacter pomeroyi PDB header:transferase Chain: D: PDB Molecule:adenosylmethionine-8-amino-7- 3 c3n5mD_ Alignment 100.0 28 oxononanoate aminotransferase; PDBTitle: crystals structure of a bacillus anthracis aminotransferase PDB header:transferase Chain: A: PDB Molecule:putative aminotransferase; 4 c3fcrA_ 100.0 24 Alignment PDBTitle: crystal structure of putative aminotransferase (yp_614685.1) from2 silicibacter sp. tm1040 at 1.80 a resolution PDB header:transferase Chain: A: PDB Molecule:omega transaminase; 5 c4a6tA_ 100.0 27 Alignment PDBTitle: crystal structure of the omega transaminase from2 chromobacterium violaceum in complex with plp PDB header:transferase Chain: B: PDB Molecule:aminotransferase; 6 c3i5tB_ 100.0 25 Alignment PDBTitle: crystal structure of aminotransferase prk07036 from rhodobacter2 sphaeroides kd131 PDB header:transferase Chain: A: PDB Molecule:adenosylmethionine-8-amino-7- oxononanoate
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2003/0198970 A1 Roberts (43) Pub
    US 2003O19897OA1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0198970 A1 Roberts (43) Pub. Date: Oct. 23, 2003 (54) GENOSTICS clinical trials on groups or cohorts of patients. This group data is used to derive a Standardised method of treatment (75) Inventor: Gareth Wyn Roberts, Cambs (GB) which is Subsequently applied on an individual basis. There is considerable evidence that a significant factor underlying Correspondence Address: the individual variability in response to disease, therapy and FINNEGAN, HENDERSON, FARABOW, prognosis lies in a person's genetic make-up. There have GARRETT & DUNNER been numerous examples relating that polymorphisms LLP within a given gene can alter the functionality of the protein 1300 ISTREET, NW encoded by that gene thus leading to a variable physiological WASHINGTON, DC 20005 (US) response. In order to bring about the integration of genomics into medical practice and enable design and building of a (73) Assignee: GENOSTIC PHARMA LIMITED technology platform which will enable the everyday practice (21) Appl. No.: 10/206,568 of molecular medicine a way must be invented for the DNA Sequence data to be aligned with the identification of genes (22) Filed: Jul. 29, 2002 central to the induction, development, progression and out come of disease or physiological States of interest. Accord Related U.S. Application Data ing to the invention, the number of genes and their configu rations (mutations and polymorphisms) needed to be (63) Continuation of application No. 09/325,123, filed on identified in order to provide critical clinical information Jun. 3, 1999, now abandoned. concerning individual prognosis is considerably less than the 100,000 thought to comprise the human genome.
    [Show full text]
  • Metabolic Network-Based Stratification of Hepatocellular Carcinoma Reveals Three Distinct Tumor Subtypes
    Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes Gholamreza Bidkhoria,b,1, Rui Benfeitasa,1, Martina Klevstigc,d, Cheng Zhanga, Jens Nielsene, Mathias Uhlena, Jan Borenc,d, and Adil Mardinoglua,b,e,2 aScience for Life Laboratory, KTH Royal Institute of Technology, SE-17121 Stockholm, Sweden; bCentre for Host-Microbiome Interactions, Dental Institute, King’s College London, SE1 9RT London, United Kingdom; cDepartment of Molecular and Clinical Medicine, University of Gothenburg, SE-41345 Gothenburg, Sweden; dThe Wallenberg Laboratory, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden; and eDepartment of Biology and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden Edited by Sang Yup Lee, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea, and approved November 1, 2018 (received for review April 27, 2018) Hepatocellular carcinoma (HCC) is one of the most frequent forms of of markers associated with recurrence and poor prognosis (13–15). liver cancer, and effective treatment methods are limited due to Moreover, genome-scale metabolic models (GEMs), collections tumor heterogeneity. There is a great need for comprehensive of biochemical reactions, and associated enzymes and transporters approaches to stratify HCC patients, gain biological insights into have been successfully used to characterize the metabolism of subtypes, and ultimately identify effective therapeutic targets. We HCC, as well as identify drug targets for HCC patients (11, 16–18). stratified HCC patients and characterized each subtype using tran- For instance, HCC tumors have been stratified based on the uti- scriptomics data, genome-scale metabolic networks and network lization of acetate (11). Analysis of HCC metabolism has also led topology/controllability analysis.
    [Show full text]
  • Alanine and Aspartate Aminotransferase and Glutamine-Cycling Pathway: Their Roles in Pathogenesis of Metabolic Syndrome
    Online Submissions: http://www.wjgnet.com/1007-9327office World J Gastroenterol 2012 August 7; 18(29): 3775-3781 [email protected] ISSN 1007-9327 (print) ISSN 2219-2840 (online) doi:10.3748/wjg.v18.i29.3775 © 2012 Baishideng. All rights reserved. FIELD OF VISION Alanine and aspartate aminotransferase and glutamine-cycling pathway: Their roles in pathogenesis of metabolic syndrome Silvia Sookoian, Carlos J Pirola Silvia Sookoian, Department of Clinical and Molecular Hepa- factors such as obesity, insulin resistance (IR), high tology, Institute of Medical Research A Lanari-IDIM, Univer- blood pressure, and dyslipidemia were associated with sity of Buenos Aires-National Council of Scientific and Tech- several metabolites, including branched-chain amino nological Research (CONICET), Ciudad Autónoma de Buenos acids, other hydrophobic amino acids, tryptophan Aires 1427, Argentina breakdown products, and nucleotide metabolites. In Carlos J Pirola, Department of Molecular Genetics and Biol- addition, the authors found a significant association of ogy of Complex Diseases, Institute of Medical Research A IR traits with glutamine, glutamate and the glutamine- Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Au- to-glutamate ratio. These data provide new insight into tónoma de Buenos Aires 1427, Argentina the pathogenesis of MS-associated phenotypes and in- Author contributions: Sookoian S and Pirola CJ designed the troduce a crucial role of glutamine-cycling pathway as study, analyzed
    [Show full text]
  • Recombinant Production of Eight Human
    Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism Stefano Donini, Manuela Ferrari, Chiara Fedeli, Marco Faini, Ilaria Lamberto, Ada Serena Marletta, Lara Mellini, Michela Panini, Riccardo Percudani, Loredano Pollegioni, et al. To cite this version: Stefano Donini, Manuela Ferrari, Chiara Fedeli, Marco Faini, Ilaria Lamberto, et al.. Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involve- ment in glyoxylate metabolism. Biochemical Journal, Portland Press, 2009, 422 (2), pp.265-272. 10.1042/BJ20090748. hal-00479195 HAL Id: hal-00479195 https://hal.archives-ouvertes.fr/hal-00479195 Submitted on 30 Apr 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Biochemical Journal Immediate Publication. Published on 23 Jun 2009 as manuscript BJ20090748 Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism. Stefano Donini *, Manuela Ferrari *, Chiara Fedeli *, Marco Faini *‡ , Ilaria Lamberto *, Ada Serena Marletta *, Lara Mellini *, Michela Panini *, Riccardo Percudani *, Loredano Pollegioni †, Laura Caldinelli †, Stefania Petrucco *1 and Alessio Peracchi *2 * Department of Biochemistry and Molecular Biology, University of Parma, 43100 Parma, Italy † The Protein Factory - Department of Biotechnology and Molecular Sciences, University of Insubria, 21100 Varese, Italy.
    [Show full text]
  • AGXT Gene Alanine--Glyoxylate and Serine--Pyruvate Aminotransferase
    AGXT gene alanine--glyoxylate and serine--pyruvate aminotransferase Normal Function The AGXT gene provides instructions for making an enzyme called serine-pyruvate aminotransferase. This enzyme is found in liver cells, specifically within cell structures called peroxisomes. These structures are important for several cellular activities, such as ridding the cell of toxic substances and helping to break down certain fats. In the peroxisome, serine-pyruvate aminotransferase converts a compound called glyoxylate to the protein building block (amino acid) glycine. Health Conditions Related to Genetic Changes Primary hyperoxaluria More than 175 mutations in the AGXT gene have been found to cause primary hyperoxaluria type 1. This condition is caused by the overproduction of a substance called oxalate. Excess amounts of this substance lead to kidney and bladder stones, which can begin anytime from childhood to early adulthood with kidney disease developing at any age. Deposition of oxalate in multiple other tissues throughout the body (systemic oxalosis) can cause additional health problems. Most of the AGXT gene mutations decrease or eliminate serine-pyruvate aminotransferase activity, which impairs the conversion of glyoxylate to glycine. Other mutations cause the enzyme to be misplaced in cells, transporting it to structures called mitochondria instead of to peroxisomes. While the enzyme in the mitochondria retains activity, it cannot access glyoxylate, which is in peroxisomes. All AGXT gene mutations result in the accumulation of glyoxylate, which is converted to oxalate instead of glycine. The oxalate is filtered through the kidneys and is either excreted in urine as a waste product or combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones.
    [Show full text]
  • Mutational Analysis of AGXT in Two Chinese Families with Primary
    Li et al. BMC Nephrology 2014, 15:92 http://www.biomedcentral.com/1471-2369/15/92 RESEARCH ARTICLE Open Access Mutational analysis of AGXT in two Chinese families with primary hyperoxaluria type 1 Guo-min Li1, Hong Xu1*, Qian Shen1, Yi-nv Gong1, Xiao-yan Fang1, Li Sun1, Hai-mei Liu1 and Yu An2* Abstract Background: Primary hyperoxaluria type 1 is a rare autosomal recessive disease of glyoxylate metabolism caused by a defect in the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) that leads to hyperoxaluria, recurrent urolithiasis, and nephrocalcinosis. Methods: Two unrelated patients with recurrent urolithiasis, along with members of their families, exhibited mutations in the AGXT gene by PCR direct sequencing. Results: Two heterozygous mutations that predict truncated proteins, p.S81X and p.S275delinsRAfs, were identified in one patient. The p.S81X mutation is novel. Two heterozygous missense mutations, p.M1T and p.I202N, were detected in another patient but were not identified in her sibling. These four mutations were confirmed to be of paternal and maternal origin. Conclusions: These are the first cases of primary hyperoxaluria type 1 to be diagnosed by clinical manifestations and AGXT gene mutations in mainland China. The novel p.S81X and p.I202N mutations detected in our study extend the spectrum of known AGXT gene mutations. Keywords: AGXT gene, Chinese children, Mutational analysis, Novel mutation, Primary hyperoxaluria type 1 Background [5,7-9]. Excessive oxalate excretion is an indicator of Primary hyperoxaluria type 1 (PH1; MIM# 259900) is an this disease; however, the test is not specific for PH1 autosomal recessive disorder of glyoxylate metabolism, and may have misleading results because oxalate excretion leading to the overproduction of endogenous oxalate; may be reduced during renal failure [2,10,11].
    [Show full text]