DOCSLIB.ORG

Hereditary Spastic Paraplegias: Clinical Spectrum in Sudan, Further Deciphering of the Molecular Bases of Autosomal Recessive Forms and New Genes Emerging

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hereditary Spastic Paraplegias: Clinical Spectrum in Sudan, Further Deciphering of the Molecular Bases of Autosomal Recessive Forms and New Genes Emerging Hereditary spastic paraplegias : clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging Liena Elbaghir Omer Elsayed To cite this version: Liena Elbaghir Omer Elsayed. Hereditary spastic paraplegias : clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging. Neurons and Cognition [q-bio.NC]. Université Pierre et Marie Curie - Paris VI; University of Khartoum, 2016. English. NNT : 2016PA066056. tel-01438739 HAL Id: tel-01438739 https://tel.archives-ouvertes.fr/tel-01438739 Submitted on 18 Jan 2017 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. Université Pierre et Marie Curie University of Khartoum Cerveau-Cognition-Comportement (ED3C) Institut du Cerveau et de la Moelle Epinière / Equipe Bases Moléculaires, Physiopathologie Et Traitement Des Maladies Neurodégénératives Hereditary spastic paraplegias: clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging Par Liena ELBAGHIR OMER ELSAYED Thèse de doctorat de Neuroscience Dirigée par Dr. Giovanni STEVANIN, Professor. Ammar ELTAHIR AHMED Présentée et soutenue publiquement le 27 avril 2016, devant un jury composé de: Pr.LEGUERN, Eric, PU-PH Représentant de l’UPMC Pr.KLEBE, Stephan, PU-PH Rapporteur Pr.KOENIG, Michel, PU-PH Rapporteur Pr.BOESPFLUG-TANGUY, Odile, PU-PH Examinateur Pr.ELTAYEB IBRAHIM, Mutaser, PU Examinateur Pr.ELTAHIR AHMED, Ammar, PU-PH Co-directeur de thèse Dr.STEVANIN, Giovanni, DR Directeur Dedication To my parents, husband, kids. I II Acknowledgement I am grateful to the members of my thesis defense jury who have kindly accepted to read and assess my PhD manuscript. I would also like to express my sincere gratitude to my thesis directors Dr.Giovanni Stevanin and professor Ammar Eltahir Ahmed for kindly accepting to guide me throughout my journey in this challenging PhD project. They have been quite supportive at each step and have given me a great deal of independence which has allowed me to gain the required skills in project management and trouble shooting and be prepared for the next step. Dr.Giovanni Stevanin has struggled to get me the budget necessary for my experiments and has gently helped me at each step despite his rather busy schedule. I enjoyed much his humble friendly attitude despite his vast knowledge in our weekly discussions that we had in the last two months of my stay in France. Pr.Ammar Eltahir has kindly taken the burden of the neurophysiological investigations and opened his heart and clinic for all patients included in the cohort. He has been quite supportive and enthusiastic to help me by all means and efficiently contributed to the recruitment of new families. I would like to thanks Pr.Alexis Brice for accepting to collaborate and acquaint me in his team and even taking all the effort to come to Sudan to finalize the collaboration. My gratitude is great for Prof. Victor Patterson who has practically started the collaboration by introducing me to Pr.Brice. He has been extremely supportive and encouraging. All my appreciation is conduced to my mentors Pr.Muntaser Eltayeb Ibrahim and Pr.Mustafa Idris Elbashir who embraced and supported me from the beginning when the project was just an ambitious day dreaming. Our collaborating Sudanese clinicians are the corner stone in this research. The three lively neuropaediatricians (Dr.Inaam Gashey, Dr.Maha Elseed and Dr.Ahlam Hamed ), the humane Dr.Sarah Misbah, Pr.Mustafa Salih, Pr.Mohamed Nagib and his team, Dr. Hassab Elrasoul Siddig, Pr. Farooq Yasin and all the referring physicians, the radiologists, the ophthalmologists and the neurophysiologists all have contributed significantly to establish this project. My sincere gratitude is conducted to the Sudanese patients and their families who were as kind as a Sudanese can be expected. Prof. Alexandra Durr and Prof. Odile Boespflug-Tanguy (and her team especially Imen Dorboz) have not saved any effort to help me build my expertise in clinical neurogenetic and neuropaediatrics. Pr.Eric Leguern valuable tips with his sense of humour were priceless. Prof. Anjon Audhya team (USA) has kindly performed all the biochemical functional studies for the TFG protein and with the Parkinson team (Dr.Suzanne Lesage and her team) has yielded our successful reports so thanks to their efforts. The assistants of Alexis Brice team (Lydia Guennec, Marie-Luce Poupinel-Descambres and Antoine Guisier) have been professional and if not for the efforts of Lydia Guennec in my registration for the PhD I would have been unable to continue. The French embassy in Sudan and Campus France and the University of Khartoum provided me with the scholarship that has enabled me to come and do the PhD study in France. III My acknowledgement to the funding agents of the study: the France-Parkinson Association (to AB), the Agence Nationale de la Recherche (SPATAX-QUEST project, to GS), the Verum Foundation (to GS and AB), the Roger de Spoelberg Foundation (R12123DD, to AB), the French Academy of Sciences (to AB), the European Union (Neuromics projects, OMICS call, to AB) and the European Joint Programme - Neurodegenerative Disease Research (JPND-COURAGE-PD) project and Programme d’Investissement d’Avenir IHU-A-ICM (ANR-10-IAIHU-06). I would like to transmit my gratitude to team of the DNA and Cell bank (with special regards to the friendly Sylvie Forlani and Christelle Dussert), the laboratory and bioinformatics staff of the sequencing platform (ICM) in which we performed all the next generation techniques and the bioinformatic analysis, the platform P3S where we had the homozygosity mapping experiments performed with the help of Dr.Wassila Carpentier (who has done big efforts not only to explain and train but also has given me valuable tips for my thesis writing). Working with the team of Dr.Giovanni Stevanin has been a pleasure. They have become my second family. Professionally, Marie Coutelier and Christelle Tesson helped me in the first steps of my PhD and have been quite cooperative whenever I needed. The moments that I had with Marie were great and extremely pleasant. With Marie I discovered that Paris is truly described the city of light and because of that I stated to fall in love with the quiet lighted streets at night. The help that I have received from Mathilde Mairey with a beautiful smile and a comforting attitude of a friend cannot be described by words. Her efforts to help me in the last months of my PhD make me run out of expressions. Sawssan Ben Romdhan has been the support (with a friendly spirit) that I needed at a time when I was so desperate because of the accumulating work. Dr. Frédéric Darios and his professional group have helped and trained me on the basics of manipulations of cells and functional experiments. Special thanks are conducted to the nice Typhaine Esteves. Livia Parodi, Federica Barreca, Graziella Mongone and Paola have made me believe that Italians are all kind. The special memories, help, great laughter and the discussions I had with Khalid Hamid El-Hachimi, Livia Parodi, Celine Lustremant, Valérie Drouet, Claire Pujol, Claire Sopie Davoine, , Khadija Tahiri, Sara Morais, Oriane Trouillard, Annie Sittler, Remi Valter, Julien Branchu make me grateful to them and I feel sad and tearful when I imagine that we can’t be together anymore as we used to be. Special thanks to Claire Pujol for helping me with the final editing of the manuscript. She helped me at the critical moments of extreme fatigue and exhaustion with unforgettable friendship spirit. My team members in Sudan have been the scaffolding unit of all the work. Ashraf Kambalawy, Mahmoud Koko, Rayan Abubakar established the team with me and their professional attitude, hard working, highly committed and loyalty made me surmount all the obstacles. All the younger members of my team have worked extremely hard just to make our work successful without waiting for any reward and they have represented our team in conferences and workshops in a distinct way (Arwa Babai, Zulfa Mohamed, Hiba Malik, Israa Zuhair, Amal Salah, Ahmed Khalid, Elhami Abdalmuti, Lina Salah, Duaa Mustafa, Mayada Osama, Nabila Mohamed Hasan, Abdelhamid Mohamed and the two under-graduates Malka Osman and Eman Osama). Finally but most importantly, I would like to say honestly and proudly say that if not for the support of my family I would have done literally nothing. They have set an example of a great family who would sacrifice for the sake of others. My husband I would describe as a great man. Not only has he sacrificed all his rights of a stable situation with a settled wife but also IV he supported me psychologically and financially. My parents ElBaghir Omer Elsayed and Fatma Elsaraj have taken care of my kids and I would say my mother deserves a medal of honour for taking in charge the responsibilities of my kids’ studies and have made them brilliant youngsters better than what I could have done. My kids (Tull, Abdelaziz and Yusr) have encouraged me to go on when I was in despair and they insisted that I continue to help the patients. My parents in law (Abdelaziz Tangasawi and Asia Abdallah) took in charge a significant deal of my responsibly towards my husband and kids in parenting manner.
Load more

Recommended publications
  • PLATFORM ABSTRACTS Abstract Abstract Numbers Numbers Tuesday, November 6 41
    American Society of Human Genetics 62nd Annual Meeting November 6–10, 2012 San Francisco, California PLATFORM ABSTRACTS Abstract Abstract Numbers Numbers Tuesday, November 6 41. Genes Underlying Neurological Disease Room 134 #196–#204 2. 4:30–6:30pm: Plenary Abstract 42. Cancer Genetics III: Common Presentations Hall D #1–#6 Variants Ballroom 104 #205–#213 43. Genetics of Craniofacial and Wednesday, November 7 Musculoskeletal Disorders Room 124 #214–#222 10:30am–12:45 pm: Concurrent Platform Session A (11–19): 44. Tools for Phenotype Analysis Room 132 #223–#231 11. Genetics of Autism Spectrum 45. Therapy of Genetic Disorders Room 130 #232–#240 Disorders Hall D #7–#15 46. Pharmacogenetics: From Discovery 12. New Methods for Big Data Ballroom 103 #16–#24 to Implementation Room 123 #241–#249 13. Cancer Genetics I: Rare Variants Room 135 #25–#33 14. Quantitation and Measurement of Friday, November 9 Regulatory Oversight by the Cell Room 134 #34–#42 8:00am–10:15am: Concurrent Platform Session D (47–55): 15. New Loci for Obesity, Diabetes, and 47. Structural and Regulatory Genomic Related Traits Ballroom 104 #43–#51 Variation Hall D #250–#258 16. Neuromuscular Disease and 48. Neuropsychiatric Disorders Ballroom 103 #259–#267 Deafness Room 124 #52–#60 49. Common Variants, Rare Variants, 17. Chromosomes and Disease Room 132 #61–#69 and Everything in-Between Room 135 #268–#276 18. Prenatal and Perinatal Genetics Room 130 #70–#78 50. Population Genetics Genome-Wide Room 134 #277–#285 19. Vascular and Congenital Heart 51. Endless Forms Most Beautiful: Disease Room 123 #79–#87 Variant Discovery in Genomic Data Ballroom 104 #286–#294 52.
    [Show full text]
  • Supplemental Table S1
    Entrez Gene Symbol Gene Name Affymetrix EST Glomchip SAGE Stanford Literature HPA confirmed Gene ID Profiling profiling Profiling Profiling array profiling confirmed 1 2 A2M alpha-2-macroglobulin 0 0 0 1 0 2 10347 ABCA7 ATP-binding cassette, sub-family A (ABC1), member 7 1 0 0 0 0 3 10350 ABCA9 ATP-binding cassette, sub-family A (ABC1), member 9 1 0 0 0 0 4 10057 ABCC5 ATP-binding cassette, sub-family C (CFTR/MRP), member 5 1 0 0 0 0 5 10060 ABCC9 ATP-binding cassette, sub-family C (CFTR/MRP), member 9 1 0 0 0 0 6 79575 ABHD8 abhydrolase domain containing 8 1 0 0 0 0 7 51225 ABI3 ABI gene family, member 3 1 0 1 0 0 8 29 ABR active BCR-related gene 1 0 0 0 0 9 25841 ABTB2 ankyrin repeat and BTB (POZ) domain containing 2 1 0 1 0 0 10 30 ACAA1 acetyl-Coenzyme A acyltransferase 1 (peroxisomal 3-oxoacyl-Coenzyme A thiol 0 1 0 0 0 11 43 ACHE acetylcholinesterase (Yt blood group) 1 0 0 0 0 12 58 ACTA1 actin, alpha 1, skeletal muscle 0 1 0 0 0 13 60 ACTB actin, beta 01000 1 14 71 ACTG1 actin, gamma 1 0 1 0 0 0 15 81 ACTN4 actinin, alpha 4 0 0 1 1 1 10700177 16 10096 ACTR3 ARP3 actin-related protein 3 homolog (yeast) 0 1 0 0 0 17 94 ACVRL1 activin A receptor type II-like 1 1 0 1 0 0 18 8038 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 1 0 0 0 0 19 8751 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 1 0 0 0 0 20 8728 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 1 0 0 0 0 21 81792 ADAMTS12 ADAM metallopeptidase with thrombospondin type 1 motif, 12 1 0 0 0 0 22 9507 ADAMTS4 ADAM metallopeptidase with thrombospondin type 1
    [Show full text]
  • NIH Public Access Author Manuscript Science
    NIH Public Access Author Manuscript Science. Author manuscript; available in PMC 2014 September 08. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Science. 2014 January 31; 343(6170): 506–511. doi:10.1126/science.1247363. Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders A full list of authors and affiliations appears at the end of the article. # These authors contributed equally to this work. Abstract Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease. Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative disorders with prevalence between 3 and 10 per 100,000 individuals (1). Hallmark features are axonal degeneration and progressive lower limb spasticity resulting from a loss of corticospinal tract (CST) function. HSP is classified into two broad categories, uncomplicated and complicated, on the basis of the presence of additional clinical features such as intellectual disability, seizures, ataxia, peripheral neuropathy, skin abnormalities, and visual defects.
    [Show full text]
  • Identification of the Drosophila Melanogaster Homolog of the Human Spastin Gene
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by RERO DOC Digital Library Dev Genes Evol (2003) 213:412–415 DOI 10.1007/s00427-003-0340-x EXPRESSION NOTE Lars Kammermeier · Jrg Spring · Michael Stierwald · Jean-Marc Burgunder · Heinrich Reichert Identification of the Drosophila melanogaster homolog of the human spastin gene Received: 14 April 2003 / Accepted: 5 May 2003 / Published online: 5 June 2003 Springer-Verlag 2003 Abstract The human SPG4 locus encodes the spastin gene encoding spastin. This gene is expressed ubiqui- gene, which is responsible for the most prevalent form tously in fetal and adult human tissues (Hazan et al. of autosomal dominant hereditary spastic paraplegia 1999). The highest expression levels are found in the (AD-HSP), a neurodegenerative disorder. Here we iden- brain, with selective expression in the cortex and striatum. tify the predicted gene product CG5977 as the Drosophila In the spinal cord, spastin is expressed exclusively in homolog of the human spastin gene, with much higher nuclei of motor neurons, suggesting that the strong sequence similarities than any other related AAA domain neurodegenerative defects observed in patients are caused protein in the fly. Furthermore we report a new potential by a primary defect of spastin in neurons (Charvin et al. transmembrane domain in the N-terminus of the two 2003). The human spastin gene encodes a predicted 616- homologous proteins. During embryogenesis, the expres- amino-acid long protein and is a member of the large sion pattern of Drosophila spastin becomes restricted family of proteins with an AAA domain (ATPases primarily to the central nervous system, in contrast to the Associated with diverse cellular Activities).
    [Show full text]
  • HOOK3 Is a Scaffold for the Opposite-Polarity Microtubule-Based
    bioRxiv preprint doi: https://doi.org/10.1101/508887; this version posted December 31, 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. HOOK3 is a scaffold for the opposite-polarity microtubule-based motors cytoplasmic dynein and KIF1C Agnieszka A. Kendrick1, William B. Redwine1,2†, Phuoc Tien Tran1‡, Laura Pontano Vaites2, Monika Dzieciatkowska4, J. Wade Harper2, and Samara L. Reck-Peterson1,3,5 1Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, 92093. 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115. 3Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093. 4Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045. 5Howard Hughes Medical Institute †Present address: Stowers Institute for Medical Research, Kansas City, MO 64110 ‡Present address: Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138. *Correspondence to: Samara Reck-Peterson 9500 Gilman Drive, Leichtag 482 La Jolla CA, 92093 [email protected]; https://orcid.org/0000-0002-1553-465X 1 bioRxiv preprint doi: https://doi.org/10.1101/508887; this version posted December 31, 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.
    [Show full text]
  • Maspardin Is Mutated in Mast Syndrome, a Complicated Form of Hereditary Spastic Paraplegia Associated with Dementia Michael A
    Am. J. Hum. Genet. 73:1147–1156, 2003 Maspardin Is Mutated in Mast Syndrome, a Complicated Form of Hereditary Spastic Paraplegia Associated with Dementia Michael A. Simpson,1 Harold Cross,3 Christos Proukakis,1,2 Anna Pryde,1 Ruth Hershberger,4 Arnaud Chatonnet,5 Michael A. Patton,1 and Andrew H. Crosby1 1Department of Medical Genetics, St. George’s Hospital Medical School, University of London, and 2Department of Clinical Neurosciences, Royal Free and University College Medical School, London; 3Department of Ophthalmology, University of Arizona School of Medicine, Tucson; 4Windows of Hope Genetic Studies, Baltic, OH; and 5Departement de Physiologie Animale, Institut National de la Recherche Agronomique, Montpellier, France Mast syndrome is an autosomal recessive, complicated form of hereditary spastic paraplegia with dementia that is present at high frequency among the Old Order Amish. Subtle childhood abnormalities may be present, but the main features develop in early adulthood. The disease is slowly progressive, and cerebellar and extrapyramidal signs are also found in patients with advanced disease. Patients have a thin corpus callosum and white-matter abnormalities, as seen on magnetic resonance imaging. Using an extensive Amish pedigree, we have mapped the Mast syndrome locus (SPG21) to a small interval of chromosome 15q22.31 that encompasses just three genes. Sequence analysis of the three transcripts revealed that all 14 affected cases were homozygous for a single base-pair insertion (601insA) in the acid-cluster protein of 33 kDa (ACP33) gene. This frameshift results in the premature termination (fs201- 212X213) of the encoded product, which is designated “maspardin” (Mast syndrome, spastic paraplegia, autosomal recessive with dementia), and has been shown elsewhere to localize to intracellular endosomal/trans-Golgi trans- portation vesicles and may function in protein transport and sorting.
    [Show full text]
  • Product Datasheet KIF1C Antibody NB100-57510
    Product Datasheet KIF1C Antibody NB100-57510 Unit Size: 0.1 ml Store at 4C. Do not freeze. Reviews: 1 Publications: 1 Protocols, Publications, Related Products, Reviews, Research Tools and Images at: www.novusbio.com/NB100-57510 Updated 3/16/2021 v.20.1 Earn rewards for product reviews and publications. Submit a publication at www.novusbio.com/publications Submit a review at www.novusbio.com/reviews/destination/NB100-57510 Page 1 of 3 v.20.1 Updated 3/16/2021 NB100-57510 KIF1C Antibody Product Information Unit Size 0.1 ml Concentration 0.2 mg/ml Storage Store at 4C. Do not freeze. Clonality Polyclonal Preservative 0.09% Sodium Azide Isotype IgG Purity Immunogen affinity purified Buffer TBS and 0.1% BSA Product Description Host Rabbit Gene ID 10749 Gene Symbol KIF1C Species Human, Mouse Immunogen The immunogen recognized by this antibody maps to a region between residue 1053 and the C-terminus (residue 1103) of human kinesin family member 1C (lethal toxin sensitivity 1) using the numbering given in entry NP_006603.2 (GeneID 10749). Product Application Details Applications Western Blot, Immunoprecipitation Recommended Dilutions Western Blot 1:2000-1:10000, Immunoprecipitation 2 - 5 ug/mg lysate Page 2 of 3 v.20.1 Updated 3/16/2021 Images Western Blot: KIF1C Antibody [NB100-57510] - KIF1C is a novel HOOK3 -interacting protein.sfGFP-3xFLAG and full length (FL) HOOK3, HOOK3 (1-552), and HOOK3 (553-718) all tagged with sfGFP and 3xFLAG were immunoprecipitated with alpha-FLAG antibodies from transiently transfected HEK-293T cells. Western blots with alpha-HC, alpha- FAM160A2, alpha-KIF1C, and alpha-FLAG antibodies were used to determine which proteins co-immunoprecipitated with each HOOK3 construct.DOI:http://dx.doi.org/10.7554/eLife.28257.015 Image collected and cropped by CiteAb from the following publication (https://elifesciences.org/articles/28257), licensed under a CC-BY licence.
    [Show full text]
  • Environmental Influences on Endothelial Gene Expression
    ENDOTHELIAL CELL GENE EXPRESSION John Matthew Jeff Herbert Supervisors: Prof. Roy Bicknell and Dr. Victoria Heath PhD thesis University of Birmingham August 2012 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Tumour angiogenesis is a vital process in the pathology of tumour development and metastasis. Targeting markers of tumour endothelium provide a means of targeted destruction of a tumours oxygen and nutrient supply via destruction of tumour vasculature, which in turn ultimately leads to beneficial consequences to patients. Although current anti -angiogenic and vascular targeting strategies help patients, more potently in combination with chemo therapy, there is still a need for more tumour endothelial marker discoveries as current treatments have cardiovascular and other side effects. For the first time, the analyses of in-vivo biotinylation of an embryonic system is performed to obtain putative vascular targets. Also for the first time, deep sequencing is applied to freshly isolated tumour and normal endothelial cells from lung, colon and bladder tissues for the identification of pan-vascular-targets. Integration of the proteomic, deep sequencing, public cDNA libraries and microarrays, delivers 5,892 putative vascular targets to the science community.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • Pathogenic Variants in the AFG3L2 Proteolytic Domain Cause SCA28
    Neurogenetics J Med Genet: first published as 10.1136/jmedgenet-2018-105766 on 25 March 2019. Downloaded from ORIGINAL ARTICLE Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation Susanna, Tulli 1 Andrea Del Bondio,1 Valentina Baderna,1 Davide Mazza,2 Franca Codazzi,3,4 Tyler Mark Pierson,5 Alessandro Ambrosi,3 Dagmar Nolte,6 Cyril Goizet,7,8 ,Camilo Toro 9 Jonathan Baets,10,11 Tine Deconinck,10,11 Peter DeJonghe,10,11 Paola Mandich,12 Giorgio Casari,3,13 Francesca Maltecca 1,3 ► Additional material is ABSTRact wustl. edu/ ataxia/domatax. html), SCA type 28 published online only. To view Background Spinocerebellar ataxia type 28 (SCA28) (SCA28; MIM #610246) is the only one caused please visit the journal online is a dominantly inherited neurodegenerative disease by pathogenic variants in a resident mitochondrial (http:// dx. doi. org/ 10. 1136/ 1 jmedgenet- 2018- 105766). caused by pathogenic variants in AFG3L2. The AFG3L2 protein, AFG3L2. The clinical spectrum of SCA28 protein is a subunit of mitochondrial m-AAA complexes comprises slowly progressive gait and limb ataxia, For numbered affiliations see involved in protein quality control. Objective of this study and oculomotor abnormalities (eg, ophthalmopa- end of article. was to determine the molecular mechanisms of SCA28, resis and ptosis) as typical signs.2 which has eluded characterisation to date. AFG3L2 belongs to the AAA-protease subfamily Correspondence to Dr Francesca Maltecca, Division Methods
    [Show full text]
  • A Reduction in Drp1-Mediated Fission Compromises
    HMG Advance Access published June 26, 2016 Human Molecular Genetics, 2016, Vol. 0, No. 0 1–13 doi: 10.1093/hmg/ddw173 Advance Access Publication Date: 10 June 2016 Original Article ORIGINAL ARTICLE A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic Downloaded from ataxia of Charlevoix Saguenay Teisha Y. Bradshaw1, Lisa E.L. Romano1, Emma J. Duncan1, 1 3 2 3 Suran Nethisinghe , Rosella Abeti , Gregory J. Michael , Paola Giunti , http://hmg.oxfordjournals.org/ Sascha Vermeer4 and J. Paul Chapple1,* 1William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, United Kingdom, 2Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom, 3Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, United Kingdom and 4Department of Clinical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands at University College London on December 9, 2016 *To whom correspondence should be addressed at: Tel: þ44 2078826242; Fax: þ44 207 882 6197; Email [email protected] Abstract The neurodegenerative disease autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is caused by loss of function of sacsin, a modular protein that is required for normal mitochondrial network organization. To further understand cellular consequences of loss of sacsin, we performed microarray analyses in sacsin knockdown cells and ARSACS patient fibroblasts. This identified altered transcript levels for oxidative phosphorylation and oxidative stress genes. These changes in mitochondrial gene networks were validated by quantitative reverse transcription PCR.
    [Show full text]
  • Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
    animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest.
    [Show full text]