DOCSLIB.ORG

Expanded Newborn Screening for Inherited Metabolic Disorders and Genetic Characteristics in a Southern Chinese Population

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Expanded Newborn Screening for Inherited Metabolic Disorders and Genetic Characteristics in a Southern Chinese Population Clinica Chimica Acta 494 (2019) 106–111 Contents lists available at ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/cca Expanded newborn screening for inherited metabolic disorders and genetic characteristics in a southern Chinese population T ⁎ ⁎ Yiming Lina, Quanzhi Zhenga, Tianwen Zhengb, Zhenzhu Zhenga, Weihua Lina, , Qingliu Fua, a Neonatal Disease Screening Center, Quanzhou Maternal and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China b Department of Pediatrics, Quanzhou Maternal and Children's Hospital, 700 Fengze Street, Quanzhou, Fujian Province 362000, China ARTICLE INFO ABSTRACT Keywords: To evaluate the incidence, disease spectrum, and genetic characteristics of inherited metabolic disorders (IMDs) Expanded newborn screening of newborns in Quanzhou area, China. We analyze the expanded newborn screening results of IMDs detected by Inherited metabolic disorders tandem mass spectrometry (MS/MS) during 5 years. Suspected positive patients were diagnosed through next- Tandem mass spectrometry generation sequencing and validated by Sanger sequencing. In addition, multiplex ligation-dependent probe Fatty acid oxidation disorder amplification technology has also been applied to assist in diagnosis of diseases with deletion or duplication Mutation mutations. A total of 364,545 newborns were screened, 130 IMDs were identified yielding an incidence of 1:2804. In addition, 9 cases of maternal disorders were also identified by our MS/MS newborn screening pro- gram. There were 42 newborns with amino acid disorders (1:8680), 39 with organic acid disorders (1:9347), and 49 with fatty acid oxidation disorders (1:7440). Unlike other studies, our study indicated that fatty acid oxi- dation disorder has the highest proportion (37.7%), particularly primary carnitine deficiency (PCD) with in- cidence up to 1:10,126 was the most common disorder in the region. The recurrent mutations of relatively common diseases like PCD, phenylalanine hydroxylase deficiency, short-chain acyl-CoA dehydrogenase defi- ciency, citrin deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, and multiple acyl- CoA dehydrogenase deficiency in this region were also clearly elucidated. Therefore, our data indicated that IMDs are never uncommon in Quanzhou, the disease spectrum and genetic backgrounds were clearly elucidated, contributing to the treatment and prenatal genetic counseling of these disorders in this region. 1. Introduction a considerable number of diseases. Newborn screening (NBS) is a va- luable preventive health measure for early diagnosis, which has been Inherited metabolic disorders (IMDs) are a group of genetic dis- shown to be diagnostically effective and economically efficient. In orders caused by defective enzymes, cofactors, or transporters in me- particular, the introduction of tandem mass spectrometry (MS/MS) tabolic pathways. Many IMDs have serious consequences to the affected technology enabled the simultaneous determination and quantification neonate, including lethargy, irreversible mental retardation, physical of several amino acids and acylcarnitines in a single test [1]. Conse- handicaps, coma, and even death. Albeit individually rare, IMDs are quently, MS/MS has been applied wildly for the screening of IMDs that collectively numerous. If early accurate diagnosis was made, many of include disorders of amino acids, organic acidurias, and fatty acid these severe complications can be prevented or significantly reduced in oxidiation disorders [2]. In China, MS/MS based NBS was launched in Abbreviations: IMD, Inherited metabolic disorder; NBS, Newborn screening; MS/MS, Tandem mass spectrometry; DBS, Dried blood spot; NGS, Next-generation sequencing; PCR, Polymerase chain reaction; MLPA, Multiplex ligation-dependent probe amplification; NKH, Non-ketotic hyperglycinemia; PA, Propionic academia; PPV, Positive predictive value; PAHD, Phenylalanine hydroxylase deficiency; CD, Citrin deficiency; UCD, Urea cycle disorder; BH4D, tetrahydrobiopterin deficiency; MAT I/III, Methionine adenosyltransferase I/III; OTCD, Ornithine carbamoyltransferase deficiency; SBCADD, Short/branched chain acyl-CoA dehydrogenase defi- ciency; GA-I, Glutaric acidemia type I; IBDHD, Isobutyryl-CoA dehydrogenase deficiency; 3-MCCD, 3-methylcrotonyl CoA carboxylase dedicency; IVA, Isovaleric acidemia; MMA, Methylmalonic academia; FAODs, Fatty acid oxidation disorders; PCD, Primary carnitine deficiency; MADD, Multiple acyl-CoA dehydrogenase deficiency; SCADD, Short-chain acyl-CoA dehydrogenase deficiency; VLCADD, Very-long-chain acyl-CoA dehydrogenase deficiency; CPT-I, Carnitine palmitoyl transferase-I deficiency; PTPS, 6-Pyruvoyl-tetrahydropterin synthase; LSM, Lipid storage myopathies; C2, Aceylcarnitine; C3, Propionylcarnitine; C5, Isovalerylcarnitine/2-methylbutyrylcarnitine; C5DC, Glutarylcarnitine; C5OH, 3-Hydroxyisovalerylcarnitine/3-hydroxy-2-methylbutyrylcarnitine; C0, Free carni- tine; C8, Octanoylacrnitine; C10, Decanoylcarnitine; C12, Dodecanoylcarnitine; C14, Myristoylcarnitine ⁎ Corresponding authors. E-mail addresses: [email protected] (W. Lin), [email protected] (Q. Fu). https://doi.org/10.1016/j.cca.2019.03.1622 Received 15 March 2019; Accepted 20 March 2019 Available online 21 March 2019 0009-8981/ © 2019 Published by Elsevier B.V. Y. Lin, et al. Clinica Chimica Acta 494 (2019) 106–111 2004 and the average incidence of IMDs was 1:3795 in a pilot study [3]. Table 1 However, subsequent studies have shown that the incidence and disease Positive cases detected by MS/MS newborn screening. ff spectrum of IMDs varied greatly in di erent regions of China, especially Disorders Positive Frequency between the south and north. The expanded NBS program in- cases corporating MS/MS for newborns was begun in Quanzhou since Jan- uary 2014. Herein, we report our five-year experience with MS/MS Amino acid disorders 42 1:8680 Phenylalanine hydroxylase deficiency (PAHD) 14 1:26,039 expanded NBS, which include the incidence, disease spectrum, and Citrin deficiency (CD) 10 1:36,455 genetic characteristics of IMDs. Tetrahydrobiopterin deficiency (BH4D) 4 1:91,136 Non-ketotic hyperglycinemia (NKH) 3 1:121,515 2. Materials and methods Methionine adenosyltransferase I/III (MAT I/III) 3 1:121,515 deficiency Hyperprolinemia 1 1:364,545 2.1. Newborn screening Urea cycle disorders 7 1:52,078 Citrullinemia type I (CTLN1) 2 1:182,273 In total, 364,545 infants (209,136 males and 155,409 females) born Argininosuccinate layse deficiency (ASLD) 2 1:182,273 fi in Quanzhou, China, between January 2014 to November 2018 were Ornithine transcarbamylase de ciency (OTCD) 2 1:182,273 Carbamoylphosphate synthetase deficiency (CPSD) 1 1:364,545 enrolled for expanded NBS by MS/MS. Blood samples were collected by Organic acid disorders 39 1:9347 heel stick and spotted on Whatman 903 filter paper. Blood collection for Short/branched chain acyl-CoA dehydrogenase 12 1:30,379 NBS is recommended between 3 and 7 days of life. Dried blood spot deficiency (SBCADD) (DBS) samples were delivered by cold-chain transportation to the NBS Glutaric acidemia type I (GA-I) 7 1:52,078 fi center of Quanzhou Maternity and Children's Hospital within 5 days. Isobutyryl-CoA dehydrogenase de ciency (IBDHD) 6 1:60,758 ™ 3-methylcrotonyl CoA carboxylase dedicency (3- 5 1:72,909 DBS samples were pre-processed following the instruction of NeoBase MCCD) non-derivatized MS/MS kit (PekinElmer, USA), then an ACQUITY TQD Isovaleric acidemia (IVA) 4 1:91,136 mass spectrometer (Waters, Milford, MA, USA) was used to analyze Methylmalonic academia (MMA) 3 1:121,515 amino acids and aclycarnitines in DBS samples. The cutoff values were Propionic academia (PA) 2 1:182,273 Fatty acid oxidation disorders 49 1:7440 initially set by reference to the worldwide collaborative project and Primary carnitine deficiency (PCD) 36 1:10,126 other screening centers [4,5], and were adjusted over time as the Multiple acyl-CoA dehydrogenase deficiency 5 1:72,909 number of samples increased. Newborns with clear aberrant initial (MADD) screening results were immediately referred to confirmatory tests, in- Short-chain acyl-CoA dehydrogenase deficiency 4 1:91,136 cluding biochemical and genetic analysis. Newborns with mild initial (SCADD) Very-long-chain acyl-CoA dehydrogenase deficiency 3 1:121,515 screening results were recalled for repeated test, if the second test was (VLCAD) still positive, the patient was referred to confirmatory tests. This study Carnitine palmitoyl transferase-I deficiency (CPT I) 1 1:364,545 was approved by the Ethical Committee of Quanzhou Maternity and Total numbers 130 1:2804 Children's Hospital. Written informed consents were obtained from all Total numbers including materal disorders 139 1:2623 the infants' patients. clinical symptoms. Only patients diagnosed by genetic analysis were 2.2. Genetic analysis included in this study. Genetic analysis was performed by Genuine Diagnostics Company (Hangzhou, Zhejiang, China). Briefly, DBS or peripheral whole blood of 3. Results suspected positive patients were referred to laboratory, and genomic DNA was extracted using Qiagen Blood DNA mini kits (Qiagen, Hilden, 3.1. Newborn screening Germany) according to the manufacturer's protocol. DNA samples of the probands were quantified using a Qubit® dsDNA HS Assay Kit Among the 364,545 screened newborns, 4897 newborns were sus- fi (Invitrogen, Carlsbad, CA, USA) and then were taken for next-genera- pected positive in the rst screening, yielding a positive ratio of 1.34%. tion sequencing (NGS). The target
Load more

Recommended publications
  • Genes Investigated
    BabyNEXTTM EXTENDED Investigated genes and associated diseases Gene Disease OMIM OMIM Condition RUSP gene Disease ABCC8 Familial hyperinsulinism 600509 256450 Metabolic disorder - ABCC8-related Inborn error of amino acid metabolism ABCD1 Adrenoleukodystrophy 300371 300100 Miscellaneous RUSP multisystem (C) * diseases ABCD4 Methylmalonic aciduria and 603214 614857 Metabolic disorder - homocystinuria, cblJ type Inborn error of amino acid metabolism ACAD8 Isobutyryl-CoA 604773 611283 Metabolic Disorder - RUSP dehydrogenase deficiency Inborn error of (S) ** organic acid metabolism ACAD9 acyl-CoA dehydrogenase-9 611103 611126 Metabolic Disorder - (ACAD9) deficiency Inborn error of fatty acid metabolism ACADM Acyl-CoA dehydrogenase, 607008 201450 Metabolic Disorder - RUSP medium chain, deficiency of Inborn error of fatty (C) acid metabolism ACADS Acyl-CoA dehydrogenase, 606885 201470 Metabolic Disorder - RUSP short-chain, deficiency of Inborn error of fatty (S) acid metabolism ACADSB 2-methylbutyrylglycinuria 600301 610006 Metabolic Disorder - RUSP Inborn error of (S) organic acid metabolism ACADVL very long-chain acyl-CoA 609575 201475 Metabolic Disorder - RUSP dehydrogenase deficiency Inborn error of fatty (C) acid metabolism ACAT1 Alpha-methylacetoacetic 607809 203750 Metabolic Disorder - RUSP aciduria Inborn error of (C) organic acid metabolism ACSF3 Combined malonic and 614245 614265 Metabolic Disorder - methylmalonic aciduria Inborn error of organic acid metabolism 1 ADA Severe combined 608958 102700 Primary RUSP immunodeficiency due
    [Show full text]
  • 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]
  • Dietary Amylose:Amylopectin Ratio Influences the Expression of Amino Acid Transporters and Enzyme Activities for Amino Acid Meta
    Downloaded from British Journal of Nutrition, page 1 of 11 doi:10.1017/S0007114521002087 https://www.cambridge.org/core © The Author(s), 2021. Published by Cambridge University Press on behalf of The Nutrition Society. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Dietary amylose:amylopectin ratio influences the expression of amino acid transporters and enzyme activities for amino acid metabolism in the gastrointestinal tract of goats . IP address: 170.106.202.226 Xiaokang Lv1,2, Chuanshe Zhou1,2*, Tao Ran3, Jinzhen Jiao1, Yong Liu1, Zhiliang Tan1, Shaoxun Tang1, Jinhe Kang1, Jingjing Xie1, Liang Chen1, Ao Ren4, Qixiang Xv1,2 and Zhiwei Kong1 1CAS Key Laboratory of Agro-ecological Processes in Subtropical Region, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Hunan Provincial Key Laboratory of Animal Nutrition & Physiology , on and Metabolism, Institute of Subtropical Agriculture, the Chinese Academy of Sciences, Changsha 410125, People’s Republic of 28 Sep 2021 at 13:00:40 China 2University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China 3College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730020, People’s Republic of China 4Department of Animal Science and Technology, University of Hunan Agricultural University, Changsha 410128, People’s Republic of China , subject to the Cambridge Core terms of use, available at (Submitted 12 March 2021 – Final revision received 25 May 2021 – Accepted 8 June 2021) Abstract This study was designed to investigate the effects of dietary starch structure on muscle protein synthesis and gastrointestinal amino acid (AA) transport and metabolism of goats.
    [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]
  • Term Description FDR Matching Proteins in the Network Metabolic Pathways 2.40E-81 AADAT,AASS,ABAT,ACAA2, ACADL, ACADM, ACADS, AC
    Term description FDR Matching proteins in the network Metabolic pathways 2.40e-81 AADAT,AASS,ABAT,ACAA2, ACADL, ACADM, ACADS, ACADSB, ACADVL, ACAT1, ACO2, ACOT1, ACOT2, ACOX1, ACSL5, ACSL6, ACSM1, ACSM3, ACSM5, ACSS2, ACSS3, AGMAT, AGXT2, AK4, ALAS1, ALDH1B1, ALDH2, ALDH4A1, ALDH5A1, ALDH6A1, ALDOB, AMACR, AMT, APRT, ARG1, ATP5A1, ATP5B, ATP5C1, ATP5E, ATP5F1, ATP5H, ATP5J, ATP5L, ATP5O, AUH, BCKDHA, BDH1, CHDH, COX4I1, COX7C, CPS1, CS, CYCS, CYP1A2, CYP27A1, DBT, DHRS4, DLAT, DLD, DLST, DMGDH, ECHS1, EHHADH, ENO1, EPHX2, FAHD1, FASN, FDPS, FECH, FH, GBE1, GCDH, GLDC, GLS, GLS2, GLUD1, GOT2, GPAM, GPI, GPT2, H6PD, HADH, HADHA, HADHB, HIBADH, HIBCH, HMGCL, HMGCS2, HSD17B10, HSD17B12, IDH1, IDH2, IDH3A, IDH3G, IVD, MCCC1, MCCC2, MCEE, MDH2, ME1, ME3, MECR, MLYCD, MMAB, MPST, MT-ATP8, MTHFD1L, MUT, NDUFA10, NDUFA12, NDUFA13, NDUFA2, NDUFA5, NDUFA7, NDUFA9, NDUFAB1, NDUFB11, NDUFB3, NDUFS1, NDUFS2, NDUFS3, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NDUFV3, NNT, OAT, OGDH, OTC, OXSM, PC, PCCA, PCCB, PDHA1, PDHB, PDHX, PRODH2, PYCR2, PYGL, SARDH, SDHA, SDHB, SHMT2, SLC27A5, SUCLA2, SUCLG1, SUCLG2, TST, UGP2, UQCRC2, UQCRFS1, UQCRQ Carbon metabolism 4.12e-43 ACADM, ACADS, ACAT1, ACO2, ACSS2, ALDH6A1, ALDOB, AMT, CAT, CPS1, CS, DLAT, DLD, DLST, ECHS1, EHHADH, ENO1, FH, GLDC, GLUD1, GOT2, GPI, GPT2, H6PD, HADHA, HIBCH, IDH1, IDH2, IDH3A, IDH3G, MCEE, MDH2, ME1, ME2, ME3, MUT, OGDH, PC, PCCA, PCCB, PDHA1, PDHB, SDHA, SDHB, SHMT2, SUCLA2, SUCLG1, SUCLG2 Valine, leucine, and isoleucine degradation 1.44e-33 ABAT, ACAA2, ACADM, ACADS, ACADSB, ACAT1, ACSF3,
    [Show full text]
  • Chain Acyl-Coa Dehydrogenase (Mcad) Deficiency
    EXPLORING THERAPEUTIC APPROACHES FOR TREATMENT OF MEDIUM- CHAIN ACYL-COA DEHYDROGENASE (MCAD) DEFICIENCY by Heejung Kang BS, Sungkyunkwan University, South Korea, 2003 MS, Sungkyunkwan University, South Korea, 2005 MS, University of Minnesota, 2008 Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2014 UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This dissertation was presented by Heejung Kang It was defended on April 15, 2014 and approved by Dissertation Advisor: Jerry Vockley, M.D. Ph.D., Professor, Pediatrics, School of Medicine, University of Pittsburgh Committee Chair: Robert Ferrell, Ph.D., Professor, Human Genetics, Graduate School of Public Health, University of Pittsburgh David Finegold, Ph.D., Professor, Pediatrics, School of Medicine, University of Pittsburgh Al-Walid A. Mohsen, Ph.D., Research Associate Professor of Pediatrics School of Medicine, University of Pittsburgh Zsolt Urban, Ph.D., Associate Professor, Human Genetics, Graduate School of Public Health, University of Pittsburgh ii Copyright © by Heejung Kang 2014 iii Jerry Vockley, MD, PhD EXPLORING THERAPEUTIC APPROACHES FOR TREATMENT OF MEDIUM- CHAIN ACYL-COA DEHYDROGENASE (MCAD) DEFICIENCY Heejung Kang, PhD University of Pittsburgh, 2014 ABSTRACT Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a common biochemical genetic disorder in the US. Nearly 90% of alleles from MCADD patients contain a common mutation in the ACADM (c.985A>G). The change replaces a lysine with a glutamate (K304E), causing improper folding. The K304E protein can fold to a mature form and is then stable and active when expressed in a prokaryotic system with molecular chaperonins.
    [Show full text]
  • Identification of Isobutyryl-Coa Dehydrogenase and Its Deficiency
    Molecular Genetics and Metabolism 77 (2002) 68–79 www.academicpress.com Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans Tien V. Nguyen,a Brage S. Andresen,b,c Thomas J. Corydon,b Sandro Ghisla,d Nasser Abd-El Razik,d Al-Walid A. Mohsen,a Stephen D. Cederbaum,e Diane S. Roe,f Charles R. Roe,f Nicolas J. Lench,g and Jerry Vockleya,* a Department of Medical Genetics, Mayo Clinic, Rochester, MN 55905, USA b Institute for Human Genetics, Aarhus University, Aarhus, Denmark c Research Unit for Molecular Medicine, Skejby Sygehus and Aarhus University, Aarhus, Denmark d Faculty of Biology, University of Konstanz, Konstanz, Germany e Department of Pediatrics, UCLA Medical Center, Los Angeles, CA, USA f Institute of Metabolic Disease, Baylor University, Dallas, TX, USA g Molecular Medicine Unit, University of Leeds, St. JamesÕ University Hospital, Leeds, UK Received 19 July 2002; received in revised form 31 July 2002; accepted 1 August 2002 Abstract The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the a,b-dehydrogenation of acyl-CoA esters. Two homologues active in branched chain amino acid metabolism have previously been identified. We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity. Purified À1 À1 recombinant enzyme had a kcat=Km of 0.8, 0.23, and 0.04 (lM s ) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionyl- CoA, respectively, as substrates. Thus, this enzyme is an isobutyryl-CoA dehydrogenase. A single patient has previously been described whose fibroblasts exhibit a specific deficit in the oxidation of valine.
    [Show full text]
  • Common Genetic Variants in the Vitamin D Pathway Including Genome-Wide Associated Variants Are Not Associated with Breast Cancer Risk Among Chinese Women
    Author Manuscript Published OnlineFirst on August 9, 2011; DOI: 10.1158/1055-9965.EPI-11-0704 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Null Results in Brief Common genetic variants in the vitamin D pathway including genome-wide associated variants are not associated with breast cancer risk among Chinese women Tsogzolmaa Dorjgochoo1, Ryan Delahanty1, Wei Lu2, Jirong Long1, Qiuyin Cai1, Ying Zheng2, Kai Gu2, Yu-Tang Gao3, Wei Zheng1, Xiao Ou Shu1 1Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA 2Shanghai Center for Disease Control and Prevention, Shanghai, China 3Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China Running title: Vitamin D pathway gene polymorphisms and breast cancer risk Keywords: breast cancer, risk, polymorphisms, vitamin D pathway genes, 25(OH)D, GWAS. Financial Support: This research was supported by USPHS grants R01CA064277, R01CA090899, and R01CA124558. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Sample preparation and genotyping assays, using Affymetrix arrays, were conducted at the Survey and Biospecimen Shared Resource and the Vanderbilt Microarray Shared Resource, respectively, which are supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485). Corresponding author: Xiao Ou Shu Professor of Medicine Vanderbilt Epidemiology Center Vanderbilt Ingram-Cancer Center Vanderbilt University 2525 West End Avenue, 6th Floor Nashville, TN 37203, USA Tel: 615-936-0713 Fax: 615-936-8291 Email: [email protected] Conflicts of Interest: No potential conflicts of interest.
    [Show full text]
  • Development of a Targeted Second-Tier Genetic Test For
    Development of a Targeted Second-Tier Genetic Test for Conditions Examined during Newborn Screening 1Lonna Mollison, 1Chelsea Gustafson, 1Edgar A Rivera-Munoz, 1Alicia Brandt, 1Daniela DeCristo, 1Falecia Metcalf, 2Cynthia Powell, 1Jonathan Berg 1Department of Genetics, 2Department of Pediatrics and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina Introduction Figure 1. Library HEAT-Seq and SureSelectXT Comparison • Approximately four million children are born annually in the United States, preparation workflows for Agilent’s SureSelectXT most undergo state mandated newborn screening and Roche’s HEAT-Seq. A. B. C. • In 2006 the American College of Medical Genetics and Genomics (ACMG) • Time requirement for developed a recommended uniform screening panel (RUSP) to minimize SureSelectXT was about 32 hours, and variability between states for HEAT-Seq about 8 • Most RUSP conditions are detected by tandem mass spectrometry hours. • Recommended DNA • Through the use of genetic sequencing it is possible to detect the underlying input amount for genetic cause of RUSP conditions SureSelectXT was • Here we propose a step-wise approach to enhance traditional newborn about 3000ng, and for HEAT-Seq was about D. screening and integrate genetic screening into population health using cost- 250ng. effective, targeted sequencing to examine current RUSP conditions • Cost per sample for Figure 4. (A-C) The percent of bases at varying read depths for SureSelectXT HEAT-Seq and SureSelect when normalized to 5M reads (A), 50M (including all human reads (B) and 200M reads (C) for each of the 8 samples. (D) The exon baits) was about percent of targeted bases in all samples sequenced at 30 fold Core Condition Associated Gene(s) ACMG Code $333, and for HEAT- coverage were estimated normalizing the data to various values Maple Syrup Urine Disease BCKDHA, BCKDHB, DBT MSUD Seq (including MIPs) of sequenced reads.
    [Show full text]
  • Transcriptomic and Proteomic Analysis Reveals Mechanisms of Patulin- Induced Cell Toxicity in Human Embryonic Kidney Cells
    Toxins 2020, 12, x; doi: FOR PEER REVIEW S1 of S12 Supplementary Materials: Transcriptomic and Proteomic Analysis Reveals Mechanisms of Patulin- Induced Cell Toxicity in Human Embryonic Kidney Cells Nianfa Han, Ruilin Luo, Jiayu Liu, Tianmin Guo, Jiayu Feng and Xiaoli Peng 100 Control 100 5 µM PAT for 10 h Genes mappled by all clean tags Genes mappled by all clean tags Genes mapped by unambigous 80 Genes mapped by unambigous 80 clean tags clean tags 60 60 40 40 20 20 0 Percentage genes of identified (%) 0 Percentage genes of identified (%) 0 5 10 15 20 25 30 35 0 5 10 15 20 25 30 35 Total tag of number (×100 K) Total tag of number (×100 K) Figure S1. Saturation evaluation of detected gene expression. When sequencing amount reaches 2 M or higher, the number of detected genes almost ceases to increase. Toxins 2020, 12, x; doi: FOR PEER REVIEW S2 of S12 Table S1. Statistics of categorization and abundance of digital gene expression (DGE) tags. Control 5 μM PAT for 10 h Total tags Distinct tags Total tags Distinct tags number % number % number % number % Total reads 3,479,005 100.00 335,487 100.00 3,732,185 100.00 359,859 100.00 Tags containing N 3309 0.10 2757 0.82 3328 0.09 2760 0.77 Only adaptors 32 0.00 27 0.01 91 0.00 86 0.02 Copy number < 2 193,285 5.56 193,285 57.61 210,396 5.64 210,396 58.47 clean reads 3,282,379 94.35 139,418 41.56 3,518,370 94.27 146,617 40.74 Copy number (2,5) 238,686 7.27 83,877 60.16 248,991 7.08 87,676 59.80 Copy number (6,10) 160,649 4.89 21,200 15.21 169,270 4.81 22,339 15.24 Copy number (11,20) 208,339 6.35
    [Show full text]
  • Advantages of Functional Analysis in Comparison of Different Chemometric Techniques for Selecting Obesity-Related Genes of Adipose Tissue from High-Fat Diet-Fed Mice
    Biomedical Research and Therapy, 8(3):4277-4285 Open Access Full Text Article Original Research Advantages of functional analysis in comparison of different chemometric techniques for selecting obesity-related genes of adipose tissue from high-fat diet-fed mice Saravanan Dharmaraj*, Mahadeva Rao U. S. , Nordin Simbak ABSTRACT Introduction: Obesity is a lifestyle disease that is becoming prevalent nowadays and is associated with a surplus in energy balance related to lipid metabolism, inflammation and hypoxic condition, Use your smartphone to scan this resulting in maladaptive adipose tissue expansion. This study used the publicly available gene QR code and download this article dataset to identify a small subset of important genes for diagnostics or as potential targets for therapeutics. Methods: Chemometric analyses by principal component analysis (PCA), random forest (RF), and genetic algorithm (GA) were used to identify 50 genes that differentiate adipose samples from high-fat diet- and normal diet-fed mice. The first 30 important genes were studied for classifying the samples using six different classification techniques. Gene ontology (GO), pathway analysis, and protein-protein interaction studies on the 50 selected genes were subsequently done to identify important functional genes. Finally, gene regulatory effects by microRNA were assessed to confirm the genes' potential as targets for new therapeutic drugs. Results: The genes identified by RF are best for differentiating the samples, followed by PCA, with the least predictability shown by genes chosen by GA. However, PCA identified more genes with functional importance, such as the hub genes ATP5a1 and Apoa1. ATP5a1 is the main hub gene, whereas Apoa1 is involved in cholesterol metabolism.
    [Show full text]
  • Elucidating the Mitochondrial Architecture of Branched-Chain Amino Acid Metabolism Enzymes: Implications for Treatment
    ELUCIDATING THE MITOCHONDRIAL ARCHITECTURE OF BRANCHED-CHAIN AMINO ACID METABOLISM ENZYMES: IMPLICATIONS FOR TREATMENT by Stephen Paul McCalley BS Biology, University of Pittsburgh, 2013 Submitted to the Graduate Faculty of the Department of Human Genetics in the Graduate School of Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2018 UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH This dissertation was presented by Stephen Paul McCalley It was defended on February 23, 2018 and approved by Eric S Goetzman, PhD, Associate Professor, Human Genetics Graduate School of Public Health, University of Pittsburgh Candace Kammerer, PhD, Associate Professor, Human Genetics Graduate School of Public Health, University of Pittsburgh Zsolt Urban, PhD, Associate Professor, Human Genetics Graduate School of Public Health, University of Pittsburgh Dissertation Advisor: Jerry Vockley, MD, PhD, Professor, Human Genetics Graduate School of Public Health, University of Pittsburgh Copyright © by Stephen Paul McCalley 2018 Jerry Vockley, MD, PhD ELUCIDATING THE MITOCHONDRIAL ARCHITECTURE OF BRANCHED- CHAIN AMINO ACID METABOLISM ENZYMES: IMPLICATIONS FOR TREATMENT Stephen Paul McCalley, PhD University of Pittsburgh, 2018 ABSTRACT Branched chain amino acid (BCAA) metabolism occurs within the mitochondrial matrix and is comprised of 17 enzymes, some shared, organized into three pathways for the catabolism of leucine, isoleucine, and valine (LEU, ILE, and VAL respectively). However, the physical relationships of the various enzymes in the pathways are unknown. Diseases such as isovaleric academia, propionic and methylmalonic acidemias, and maple syrup urine disease are among the disorders caused by genetic deficiencies of BCAA metabolism. I examined the BCAA pathways and their physical interactions in vitro through proteomics analysis and in situ using stimulated emission depletion microscopy.
    [Show full text]