Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy
Purpose - Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses. - Methods - Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients’ fibroblasts were used to perform mass spectrometry-based proteomics. - Results - UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients’ fibroblasts. - Conclusion - Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
20 August 2022 2022 |
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| Erschienen: |
20 August 2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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| Enthalten in: |
Genetics in medicine - 24(2022), 10 vom: Okt., Seite 2079-2090 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Park, Joohyun [VerfasserIn] |
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Authors: Joohyun Park, Arianna Tucci, Valentina Cipriani, German Demidov, Clarissa Rocca, Jan Senderek, Michaela Butryn, Ana Velic, Tanya Lam, Evangelia Galanaki, Elisa Cali, Letizia Vestito, Reza Maroofian, Natalie Deininger, Maren Rautenberg, Jakob Admard, Gesa-Astrid Hahn, Claudius Bartels, Nienke J.H. van Os, Rita Horvath, Patrick F. Chinnery, May Yung Tiet, Channa Hewamadduma, Marios Hadjivassiliou, George K. Tofaris, J.C. Ambrose, P. Arumugam, E.L. Baple, M. Bleda, F. Boardman-Pretty, J.M. Boissiere, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, C.E.H. Craig, L.C. Daugherty, A. de Burca, A. Devereau, G. Elgar, R.E. Foulger, T. Fowler, P. Furió-Tarí, J.M. Hackett, D. Halai, A. Hamblin, S. Henderson, J.E. Holman, T.J.P. Hubbard, K. Ibáñez, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, L. Lahnstein, K. Lawson, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, J. Mason, E.M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, C.A. Odhams, C. Patch, D. Perez-Gil, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K.R. Smith, A. Sosinsky, W. Spooner, H.E. Stevens, A. Stuckey, R. Sultana, E.R.A. Thomas, S.R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S.A. Watters, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Nicholas W. Wood, Stefanie N. Hayer, Friedemann Bender, Benita Menden, Isabell Cordts, Katrin Klein, Huu Phuc Nguyen, Joachim K. Krauss, Christian Blahak, Tim M. Strom, Marc Sturm, Bart van de Warrenburg, Holger Lerche, Boris Maček, Matthis Synofzik, Stephan Ossowski, Dagmar Timmann, Marc E. Wolf, Damian Smedley, Olaf Riess, Ludger Schöls, Henry Houlden, Tobias B. Haack, Holger Hengel Der Titel ist Teil des Special issue: Ophthalmology Online verfügbar: 20 August 2022, Artikelversion: 4 October 2022 Gesehen am 21.08.2023 |
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| Umfang: |
12 |
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| doi: |
10.1016/j.gim.2022.07.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy |
| 264 | 1 | |c 20 August 2022 | |
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| 500 | |a Authors: Joohyun Park, Arianna Tucci, Valentina Cipriani, German Demidov, Clarissa Rocca, Jan Senderek, Michaela Butryn, Ana Velic, Tanya Lam, Evangelia Galanaki, Elisa Cali, Letizia Vestito, Reza Maroofian, Natalie Deininger, Maren Rautenberg, Jakob Admard, Gesa-Astrid Hahn, Claudius Bartels, Nienke J.H. van Os, Rita Horvath, Patrick F. Chinnery, May Yung Tiet, Channa Hewamadduma, Marios Hadjivassiliou, George K. Tofaris, J.C. Ambrose, P. Arumugam, E.L. Baple, M. Bleda, F. Boardman-Pretty, J.M. Boissiere, C.R. Boustred, H. Brittain, M.J. Caulfield, G.C. Chan, C.E.H. Craig, L.C. Daugherty, A. de Burca, A. Devereau, G. Elgar, R.E. Foulger, T. Fowler, P. Furió-Tarí, J.M. Hackett, D. Halai, A. Hamblin, S. Henderson, J.E. Holman, T.J.P. Hubbard, K. Ibáñez, R. Jackson, L.J. Jones, D. Kasperaviciute, M. Kayikci, L. Lahnstein, K. Lawson, S.E.A. Leigh, I.U.S. Leong, F.J. Lopez, F. Maleady-Crowe, J. Mason, E.M. McDonagh, L. Moutsianas, M. Mueller, N. Murugaesu, A.C. Need, C.A. Odhams, C. Patch, D. Perez-Gil, D. Polychronopoulos, J. Pullinger, T. Rahim, A. Rendon, P. Riesgo-Ferreiro, T. Rogers, M. Ryten, K. Savage, K. Sawant, R.H. Scott, A. Siddiq, A. Sieghart, D. Smedley, K.R. Smith, A. Sosinsky, W. Spooner, H.E. Stevens, A. Stuckey, R. Sultana, E.R.A. Thomas, S.R. Thompson, C. Tregidgo, A. Tucci, E. Walsh, S.A. Watters, M.J. Welland, E. Williams, K. Witkowska, S.M. Wood, M. Zarowiecki, Nicholas W. Wood, Stefanie N. Hayer, Friedemann Bender, Benita Menden, Isabell Cordts, Katrin Klein, Huu Phuc Nguyen, Joachim K. Krauss, Christian Blahak, Tim M. Strom, Marc Sturm, Bart van de Warrenburg, Holger Lerche, Boris Maček, Matthis Synofzik, Stephan Ossowski, Dagmar Timmann, Marc E. Wolf, Damian Smedley, Olaf Riess, Ludger Schöls, Henry Houlden, Tobias B. Haack, Holger Hengel | ||
| 500 | |a Der Titel ist Teil des Special issue: Ophthalmology | ||
| 500 | |a Online verfügbar: 20 August 2022, Artikelversion: 4 October 2022 | ||
| 500 | |a Gesehen am 21.08.2023 | ||
| 520 | |a Purpose - Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses. - Methods - Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients’ fibroblasts were used to perform mass spectrometry-based proteomics. - Results - UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients’ fibroblasts. - Conclusion - Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia. | ||
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