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Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- Wiessner, M. (author)
- Maroofian, R. (author)
- Ni, M. Y. (author)
- show more...
- Müller, J. S. (author)
- Stucka, R. (author)
- Beetz, C. (author)
- Efthymiou, S. (author)
- Santorelli, F. M. (author)
- Alfares, A. A. (author)
- Uhrova Meszarosova, A. (author)
- Alehabib, E. (author)
- Bakhtiari, S. (author)
- Janecke, A. R. (author)
- Otero, M. G. (author)
- Chen, J. Y. H. (author)
- Peterson, J. T. (author)
- Strom, T. M. (author)
- De Jonghe, P. (author)
- Deconinck, T. (author)
- De Ridder, W. (author)
- De Winter, J. (author)
- Pasquariello, R. (author)
- Ricca, I. (author)
- Alfadhel, M. (author)
- Van De Warrenburg, B. P. (author)
- Portier, R. (author)
- Bergmann, C. (author)
- Ghasemi Firouzabadi, S. (author)
- Jin, S. C. (author)
- Bilguvar, K. (author)
- Hamed, S. (author)
- Abdelhameed, M. (author)
- Haridy, N. A. (author)
- Maqbool, S. (author)
- Rahman, F. (author)
- Anwar, N. (author)
- Carmichael, J. (author)
- Pagnamenta, A. (author)
- Wood, N. W. (author)
- Tran Mau-Them, F. (author)
- Haack, T. (author)
- Di Rocco, M. (author)
- Ceccherini, I. (author)
- Iacomino, M. (author)
- Zara, F. (author)
- Salpietro, V. (author)
- Scala, M. (author)
- Rusmini, M. (author)
- Xu, Y. (author)
- Wang, Y. (author)
- Suzuki, Y. (author)
- Nan, H. (author)
- Ishiura, H. (author)
- Tsuji, S. (author)
- Lambert, L. (author)
- Schmitt, E. (author)
- Lacaze, E. (author)
- Küpper, H. (author)
- Dredge, D. (author)
- Skraban, C. (author)
- Goldstein, A. (author)
- Willis, M. J. H. (author)
- Grand, K. (author)
- Graham, J. M. (author)
- Lewis, R. A. (author)
- Millan, F. (author)
- Duman, Ö (author)
- Dündar, N. (author)
- Uyanik, G. (author)
- Schöls, L. (author)
- Nürnberg, P. (author)
- Nürnberg, G. (author)
- Catala Bordes, A. (author)
- Seeman, P. (author)
- Kuchar, M. (author)
- Darvish, H. (author)
- Rebelo, A. (author)
- Bouçanova, F. (author)
- Medard, J. J. (author)
- Chrast, R. (author)
- Auer-Grumbach, M. (author)
- Alkuraya, F. S. (author)
- Shamseldin, H. (author)
- Al Tala, S. (author)
- Rezazadeh Varaghchi, J. (author)
- Najafi, M. (author)
- Deschner, S. (author)
- Gläser, D. (author)
- Hüttel, W. (author)
- Kruer, M. C. (author)
- Kamsteeg, E. J. (author)
- Takiyama, Y. (author)
- Züchner, S. (author)
- Baets, J. (author)
- Synofzik, M. (author)
- Schüle, R. (author)
- Horvath, R. (author)
- Houlden, H. (author)
- Bartesaghi, L. (author)
- Lee, H. J. (author)
- Ampatzis, K. (author)
- Pierson, T. M. (author)
- Senderek, J. (author)
- show less...
- (creator_code:org_t)
- 2021-05-10
- 2021
- English.
- In: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
- Journal article (peer-reviewed)
Abstract
Subject headings
Close
- 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. © 2021 The Author(s).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- autosomal recessive
- hereditary spastic paraplegia
- HPDL
- HSP
- mitochondrial disorder
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
- Wiessner, M.
- Maroofian, R.
- Ni, M. Y.
- Pedroni, A.
- Müller, J. S.
- Stucka, R.
- show more...
- Beetz, C.
- Efthymiou, S.
- Santorelli, F. M ...
- Alfares, A. A.
- Zhu, Changlian, ...
- Uhrova Meszaroso ...
- Alehabib, E.
- Bakhtiari, S.
- Janecke, A. R.
- Otero, M. G.
- Chen, J. Y. H.
- Peterson, J. T.
- Strom, T. M.
- De Jonghe, P.
- Deconinck, T.
- De Ridder, W.
- De Winter, J.
- Pasquariello, R.
- Ricca, I.
- Alfadhel, M.
- Van De Warrenbur ...
- Portier, R.
- Bergmann, C.
- Ghasemi Firouzab ...
- Jin, S. C.
- Bilguvar, K.
- Hamed, S.
- Abdelhameed, M.
- Haridy, N. A.
- Maqbool, S.
- Rahman, F.
- Anwar, N.
- Carmichael, J.
- Pagnamenta, A.
- Wood, N. W.
- Tran Mau-Them, F ...
- Haack, T.
- Di Rocco, M.
- Ceccherini, I.
- Iacomino, M.
- Zara, F.
- Salpietro, V.
- Scala, M.
- Rusmini, M.
- Xu, Y.
- Wang, Y.
- Suzuki, Y.
- Koh, K.
- Nan, H.
- Ishiura, H.
- Tsuji, S.
- Lambert, L.
- Schmitt, E.
- Lacaze, E.
- Küpper, H.
- Dredge, D.
- Skraban, C.
- Goldstein, A.
- Willis, M. J. H.
- Grand, K.
- Graham, J. M.
- Lewis, R. A.
- Millan, F.
- Duman, Ö
- Dündar, N.
- Uyanik, G.
- Schöls, L.
- Nürnberg, P.
- Nürnberg, G.
- Catala Bordes, A ...
- Seeman, P.
- Kuchar, M.
- Darvish, H.
- Rebelo, A.
- Bouçanova, F.
- Medard, J. J.
- Chrast, R.
- Auer-Grumbach, M ...
- Alkuraya, F. S.
- Shamseldin, H.
- Al Tala, S.
- Rezazadeh Varagh ...
- Najafi, M.
- Deschner, S.
- Gläser, D.
- Hüttel, W.
- Kruer, M. C.
- Kamsteeg, E. J.
- Takiyama, Y.
- Züchner, S.
- Baets, J.
- Synofzik, M.
- Schüle, R.
- Horvath, R.
- Houlden, H.
- Bartesaghi, L.
- Lee, H. J.
- Ampatzis, K.
- Pierson, T. M.
- Senderek, J.
- show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
- MEDICAL AND HEAL ...
- and Basic Medicine
- and Neurosciences
- Articles in the publication
- Brain : a journa ...
- Brain
- By the university
- University of Gothenburg
- Karolinska Institutet
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