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Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia

Authors :
Andrea Bevot
Diana Chiang
Laurence Colleaux
Christian A. Hübner
Hans Hartmann
Zhao-Qi Wang
Tobias B. Haack
Ralf A. Husain
J. Christopher Hennings
Kevin Rostasy
Michael C. Kruer
Hossein Darvish
Olaf Riess
Andy Cheuk Him Ng
Marion Döbler-Neumann
Tim M. Strom
Lucia Laugwitz
Johannes A. Mayr
Thomas Klopstock
Xenia Kobeleva
René G. Feichtinger
Saghar Ghasemi Firouzabadi
Rebecca Buchert
Amelie J. Müller
Matias Wagner
Antje K. Huebner
Shrikant Mane
Marcus Deschauer
Ingeborg Krägeloh-Mann
Abdelkrim Saadi
Ulrich Brandl
Penelope E. Bonnen
Christian Marx
Isabell Cordts
Thomas Klockgether
Abbas Tafakhori
Thomas Meitinger
Florentine Radelfahr
Arnaud Besse
Mona Grimmel
Marc Sturm
Saskia B. Wortmann
Somayeh Bakhtiari
Francois V. Bolduc
Stefanie Beck-Woedl
Thomas Nägele
Marseille medical genetics - Centre de génétique médicale de Marseille (MMG)
Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Imagine - Institut des maladies génétiques (IMAGINE - U1163)
Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jena University Hospital [Jena]
University of Tübingen
Helmholtz-Zentrum München (HZM)
Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)
Leibniz Association
Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU)
Université d'Alger 1 (Benyoucef Benkhedda)
Universität Witten Herdecke
German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)
University Children's Hospital of Tübingen
Partenaires INRAE
Hannover Medical School [Hannover] (MHH)
Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Technische Universität München [München] (TUM)
University of Bonn
Semnan University
University of Arizona
Baylor College of Medicine (BCM)
Baylor University
University of Alberta
Tehran University of Medical Sciences (TUMS)
Yale University School of Medicine
University of Social Welfare and Rehabilitation Sciences [Tehran]
Universitätsklinikum Tübingen - University Hospital of Tübingen
Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany]
Munich Cluster for systems neurology [Munich] (SyNergy)
Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU)
Amalia Children’s Hospital [Nijmegen, The Netherlands]
Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)
Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU)
Helmholtz Zentrum München = German Research Center for Environmental Health
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Yale School of Medicine [New Haven, Connecticut] (YSM)
COLLEAUX, Laurence
Source :
The American journal of human genetics 107(2), 364-373 (2020). doi:10.1016/j.ajhg.2020.06.015, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2020, 107 (2), pp.364-373. ⟨10.1016/j.ajhg.2020.06.015⟩, Am J Hum Genet, Am. J. Hum. Genet. 107, 364-373 (2020)
Publication Year :
2020
Publisher :
Elsevier, 2020.

Abstract

International audience; We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

Details

Language :
English
ISSN :
00029297 and 15376605
Database :
OpenAIRE
Journal :
The American journal of human genetics 107(2), 364-373 (2020). doi:10.1016/j.ajhg.2020.06.015, American Journal of Human Genetics, American Journal of Human Genetics, Elsevier (Cell Press), 2020, 107 (2), pp.364-373. ⟨10.1016/j.ajhg.2020.06.015⟩, Am J Hum Genet, Am. J. Hum. Genet. 107, 364-373 (2020)
Accession number :
edsair.doi.dedup.....03a6b1699a506f1613e8922c058bf730