Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia
In: 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); (2020)
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Zugriff:
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.
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Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia
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| Autor/in / Beteiligte Person: | Bevot, Andrea ; Chiang, Diana ; Colleaux, Laurence ; Hübner, Christian A. ; Hartmann, Hans ; Wang, Zhao-Qi ; Haack, Tobias B. ; Husain, Ralf A. ; J. Christopher Hennings ; Rostasy, Kevin ; Kruer, Michael C. ; Darvish, Hossein ; Riess, Olaf ; Andy Cheuk Him Ng ; Döbler-Neumann, Marion ; Strom, Tim M. ; Laugwitz, Lucia ; Mayr, Johannes A. ; Klopstock, Thomas ; Kobeleva, Xenia ; Feichtinger, René G. ; Saghar Ghasemi Firouzabadi ; Buchert, Rebecca ; Müller, Amelie J. ; Wagner, Matias ; Huebner, Antje K. ; Mane, Shrikant ; Deschauer, Marcus ; Krägeloh-Mann, Ingeborg ; Saadi, Abdelkrim ; Brandl, Ulrich ; Bonnen, Penelope E. ; Marx, Christian ; Cordts, Isabell ; Klockgether, Thomas ; Tafakhori, Abbas ; Meitinger, Thomas ; Radelfahr, Florentine ; Besse, Arnaud ; Grimmel, Mona ; Sturm, Marc ; Wortmann, Saskia B. ; Bakhtiari, Somayeh ; Bolduc, Francois V. ; Beck-Woedl, Stefanie ; Nägele, Thomas ; 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) ; Association, Leibniz ; 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 ; University, Semnan ; University of Arizona ; Baylor College of Medicine (BCM) ; University, Baylor ; 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 |
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| Quelle: | 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); (2020) |
| Veröffentlichung: | Elsevier, 2020 |
| Medientyp: | unknown |
| ISSN: | 0002-9297 (print) ; 1537-6605 (print) |
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