Wiessner, Manuela, Maroofian, Reza, Ni, Meng-Yuan, Pedroni, Andrea, Muller, Juliane S., Stucka, Rolf, Beetz, Christian, Efthymiou, Stephanie ORCID: 0000-0003-4900-9877, Santorelli, Filippo M., Alfares, Ahmed A., Zhu, Changlian, Meszarosova, Anna Uhrova, Alehabib, Elham, Bakhtiari, Somayeh, Janecke, Andreas R., Otero, Maria Gabriela, Chen, Jin Yun Helen, Peterson, James T., Strom, Tim M., De Jonghe, Peter, Deconinck, Tine, De Ridder, Willem, De Winter, Jonathan, Pasquariello, Rossella, Ricca, Ivana ORCID: 0000-0001-8939-1447, Alfadhel, Majid, van de Warrenburg, Bart P., Portier, Ruben, Bergmann, Carsten, Firouzabadi, Saghar Ghasemi, Jin, Sheng Chih ORCID: 0000-0002-5777-7262, Bilguvar, Kaya, Hamed, Sherifa ORCID: 0000-0002-1441-3530, Abdelhameed, Mohammed, Haridy, Nourelhoda A., Maqbool, Shazia, Rahman, Fatima, Anwar, Najwa, Carmichael, Jenny, Pagnamenta, Alistair, Wood, Nick W., Mau-Them, Frederic Tran, Haack, Tobias, Di Rocco, Maja, Ceccherini, Isabella, Iacomino, Michele ORCID: 0000-0003-4788-9719, Zara, Federico ORCID: 0000-0001-9744-5222, Salpietro, Vincenzo, Scala, Marcello ORCID: 0000-0003-2194-7239, Rusmini, Marta, Xu, Yiran, Wang, Yinghong, Suzuki, Yasuhiro, Koh, Kishin, Nan, Haitian, Ishiura, Hiroyuki, Tsuji, Shoji, Lambert, Laetitia, Schmitt, Emmanuelle, Lacaze, Elodie, Kupper, Hanna, Dredge, David, Skraban, Cara, Goldstein, Amy, Willis, Mary J. H., Grand, Katheryn, Graham, John M., Lewis, Richard A., Millan, Francisca, Duman, Ozgur, Dundar, Nihal, Uyanik, Gokhan, Schols, Ludger ORCID: 0000-0001-7774-5025, Nurnberg, Peter, Nurnberg, Gudrun, Bordes, Andrea Catala, Seeman, Pavel, Kuchar, Martin, Darvish, Hossein, Rebelo, Adriana, Boucanova, Filipa, Medard, Jean-Jacques, Chrast, Roman, Auer-Grumbach, Michaela, Alkuraya, Fowzan S., Shamseldin, Hanan, Al Tala, Saeed, Varaghchi, Jamileh Rezazadeh, Najafi, Maryam, Deschner, Selina, Glaser, Dieter, Huttel, Wolfgang, Kruer, Michael C., Kamsteeg, Erik-Jan, Takiyama, Yoshihisa, Zuchner, Stephan, Baets, Jonathan, Synofzik, Matthis, Schuele, Rebecca, Horvath, Rita ORCID: 0000-0002-9841-170X, Houlden, Henry, Bartesaghi, Luca ORCID: 0000-0001-8218-4648, Lee, Hwei-Jen, Ampatzis, Konstantinos, Pierson, Tyler Mark ORCID: 0000-0003-1985-3671 and Senderek, Jan (2021). Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain, 144 (5). S. 1422 - 1435. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wiessner, ManuelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maroofian, RezaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ni, Meng-YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedroni, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller, Juliane S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stucka, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beetz, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Efthymiou, StephanieUNSPECIFIEDorcid.org/0000-0003-4900-9877UNSPECIFIED
Santorelli, Filippo M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alfares, Ahmed A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhu, ChanglianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meszarosova, Anna UhrovaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alehabib, ElhamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bakhtiari, SomayehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janecke, Andreas R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Otero, Maria GabrielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, Jin Yun HelenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterson, James T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strom, Tim M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deconinck, TineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Ridder, WillemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Winter, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasquariello, RossellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ricca, IvanaUNSPECIFIEDorcid.org/0000-0001-8939-1447UNSPECIFIED
Alfadhel, MajidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Warrenburg, Bart P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Portier, RubenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergmann, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Firouzabadi, Saghar GhasemiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jin, Sheng ChihUNSPECIFIEDorcid.org/0000-0002-5777-7262UNSPECIFIED
Bilguvar, KayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamed, SherifaUNSPECIFIEDorcid.org/0000-0002-1441-3530UNSPECIFIED
Abdelhameed, MohammedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haridy, Nourelhoda A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maqbool, ShaziaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahman, FatimaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anwar, NajwaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmichael, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pagnamenta, AlistairUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wood, Nick W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mau-Them, Frederic TranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haack, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Di Rocco, MajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ceccherini, IsabellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iacomino, MicheleUNSPECIFIEDorcid.org/0000-0003-4788-9719UNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Salpietro, VincenzoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scala, MarcelloUNSPECIFIEDorcid.org/0000-0003-2194-7239UNSPECIFIED
Rusmini, MartaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xu, YiranUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, YinghongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suzuki, YasuhiroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koh, KishinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nan, HaitianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ishiura, HiroyukiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tsuji, ShojiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lambert, LaetitiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt, EmmanuelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lacaze, ElodieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kupper, HannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dredge, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skraban, CaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldstein, AmyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willis, Mary J. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grand, KatherynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Graham, John M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewis, Richard A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Millan, FranciscaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duman, OzgurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dundar, NihalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uyanik, GokhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schols, LudgerUNSPECIFIEDorcid.org/0000-0001-7774-5025UNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bordes, Andrea CatalaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeman, PavelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuchar, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Darvish, HosseinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rebelo, AdrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boucanova, FilipaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Medard, Jean-JacquesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chrast, RomanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auer-Grumbach, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alkuraya, Fowzan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shamseldin, HananUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Al Tala, SaeedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varaghchi, Jamileh RezazadehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Najafi, MaryamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deschner, SelinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glaser, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huttel, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kruer, Michael C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kamsteeg, Erik-JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Takiyama, YoshihisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuchner, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baets, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Synofzik, MatthisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schuele, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horvath, RitaUNSPECIFIEDorcid.org/0000-0002-9841-170XUNSPECIFIED
Houlden, HenryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartesaghi, LucaUNSPECIFIEDorcid.org/0000-0001-8218-4648UNSPECIFIED
Lee, Hwei-JenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ampatzis, KonstantinosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pierson, Tyler MarkUNSPECIFIEDorcid.org/0000-0003-1985-3671UNSPECIFIED
Senderek, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-608287
DOI: 10.1093/brain/awab041
Journal or Publication Title: Brain
Volume: 144
Number: 5
Page Range: S. 1422 - 1435
Date: 2021
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2156
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
INTELLECTUAL DISABILITY; DIOXYGENASE GENE; MUTATIONS; PROTEIN; ACID; DIAGNOSIS; EXOMEMultiple languages
Clinical Neurology; NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60828

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