. 2022 Oct;24(10):2079-2090.

doi: 10.1016/j.gim.2022.07.006. Epub 2022 Aug 20.

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Joohyun Park¹, Arianna Tucci², Valentina Cipriani³, German Demidov¹, Clarissa Rocca⁴, Jan Senderek⁵, Michaela Butryn⁶, Ana Velic⁷, Tanya Lam⁸, Evangelia Galanaki⁴, Elisa Cali⁴, Letizia Vestito², Reza Maroofian⁴, Natalie Deininger¹, Maren Rautenberg¹, Jakob Admard¹, Gesa-Astrid Hahn⁹, Claudius Bartels¹⁰, Nienke J H van Os¹¹, Rita Horvath¹², Patrick F Chinnery¹³, May Yung Tiet¹², Channa Hewamadduma¹⁴, Marios Hadjivassiliou¹⁵, George K Tofaris¹⁶; Genomics England Research Consortium; Nicholas W Wood¹⁷, Stefanie N Hayer¹⁸, Friedemann Bender¹⁸, Benita Menden¹, Isabell Cordts¹⁹, Katrin Klein¹, Huu Phuc Nguyen²⁰, Joachim K Krauss²¹, Christian Blahak²², Tim M Strom²³, Marc Sturm¹, Bart van de Warrenburg¹¹, Holger Lerche²⁴, Boris Maček⁷, Matthis Synofzik¹⁸, Stephan Ossowski¹, Dagmar Timmann²⁵, Marc E Wolf²⁶, Damian Smedley², Olaf Riess²⁷, Ludger Schöls²⁸, Henry Houlden²⁹, Tobias B Haack²⁷, Holger Hengel³⁰

Collaborators, Affiliations

Collaborators

Genomics England Research Consortium:
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

Affiliations

¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
² William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
³ William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; UCL Genetics Institute, University College London, London, United Kingdom.
⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
⁵ Department of Neurology, Friedrich-Baur-Institute, University Hospital, Ludwig-Maximilian University Munich, Munich, Germany.
⁶ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
⁷ Proteome Center Tübingen, University of Tübingen, Tübingen, Germany.
⁸ Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; St George's Hospital NHS Trust, London, United Kingdom.
⁹ CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany.
¹⁰ Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.
¹¹ Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Center of Expertise for Parkinson and Movement Disorders, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
¹³ Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom; MRC Mitochondrial Biology Unit & Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
¹⁴ Sheffield Institute for Translational Neurosciences (SITraN), The University of Sheffield, Sheffield, United Kingdom; Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.
¹⁵ Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom; Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust and The University of Sheffield, Sheffield, United Kingdom.
¹⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
¹⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹⁸ Department of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Neurology, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany.
²⁰ Department of Human Genetics, Medical Faculty, Ruhr University Bochum, Bochum, Germany.
²¹ Department of Neurosurgery, Hannover Medical School, Hannover, Germany.
²² Department of Neurology, Ortenau Klinikum Lahr-Ettenheim, Lahr, Germany; Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²³ Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
²⁴ Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁵ Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
²⁶ Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany.
²⁷ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Center for Rare Diseases, University of Tübingen, Tübingen, Germany.
²⁸ Department of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Center for Rare Diseases, University of Tübingen, Tübingen, Germany. Electronic address: ludger.schoels@uni-tuebingen.de.
²⁹ William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. Electronic address: h.houlden@ucl.ac.uk.
³⁰ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

PMID: 35986737
DOI: 10.1016/j.gim.2022.07.006

Free article

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Joohyun Park et al. Genet Med. 2022 Oct.

Free article

. 2022 Oct;24(10):2079-2090.

doi: 10.1016/j.gim.2022.07.006. Epub 2022 Aug 20.

Authors

Collaborators

Genomics England Research Consortium:
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

Affiliations

¹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
² William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
³ William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; UCL Genetics Institute, University College London, London, United Kingdom.
⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
⁵ Department of Neurology, Friedrich-Baur-Institute, University Hospital, Ludwig-Maximilian University Munich, Munich, Germany.
⁶ German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany.
⁷ Proteome Center Tübingen, University of Tübingen, Tübingen, Germany.
⁸ Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom; St George's Hospital NHS Trust, London, United Kingdom.
⁹ CeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany.
¹⁰ Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany.
¹¹ Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Center of Expertise for Parkinson and Movement Disorders, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
¹³ Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom; MRC Mitochondrial Biology Unit & Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
¹⁴ Sheffield Institute for Translational Neurosciences (SITraN), The University of Sheffield, Sheffield, United Kingdom; Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom.
¹⁵ Royal Hallamshire Hospital, Sheffield Teaching Hospitals Foundation Trust, Sheffield, United Kingdom; Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Trust and The University of Sheffield, Sheffield, United Kingdom.
¹⁶ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.
¹⁷ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
¹⁸ Department of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
¹⁹ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Neurology, Klinikum rechts der Isar, Technical University Munich (TUM), Munich, Germany.
²⁰ Department of Human Genetics, Medical Faculty, Ruhr University Bochum, Bochum, Germany.
²¹ Department of Neurosurgery, Hannover Medical School, Hannover, Germany.
²² Department of Neurology, Ortenau Klinikum Lahr-Ettenheim, Lahr, Germany; Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
²³ Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
²⁴ Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
²⁵ Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
²⁶ Department of Neurology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany.
²⁷ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Center for Rare Diseases, University of Tübingen, Tübingen, Germany.
²⁸ Department of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Center for Rare Diseases, University of Tübingen, Tübingen, Germany. Electronic address: ludger.schoels@uni-tuebingen.de.
²⁹ William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. Electronic address: h.houlden@ucl.ac.uk.
³⁰ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Department of Neurodegenerative Diseases, Center for Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.

PMID: 35986737
DOI: 10.1016/j.gim.2022.07.006

Erratum in

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.
Park J, Tucci A, Cipriani V, Demidov G, Rocca C, Senderek J, Butryn M, Velic A, Lam T, Galanaki E, Cali E, Vestito L, Maroofian R, Deininger N, Rautenberg M, Admard J, Hahn GA, Bartels C, van Os NJH, Horvath R, Chinnery PF, Tiet MY, Hewamadduma C, Hadjivassiliou M, Downes SM, Németh AH, Tofaris GK; Genomics England Research Consortium; Wood NW, Hayer SN, Bender F, Menden B, Cordts I, Klein K, Nguyen HP, Krauss JK, Blahak C, Strom TM, Sturm M, van de Warrenburg B, Lerche H, Maček B, Synofzik M, Ossowski S, Timmann D, Wolf ME, Smedley D, Riess O, Schöls L, Houlden H, Haack TB, Hengel H. Park J, et al. Genet Med. 2023 Oct;25(10):100961. doi: 10.1016/j.gim.2023.100961. Epub 2023 Aug 31. Genet Med. 2023. PMID: 37650884 No abstract available.

Abstract

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.

Keywords: Gene burden; Proteomics; Spastic ataxia; UCHL1.

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Conflict of Interest The authors declare no conflicts of interest.

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Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Collaborators

Affiliations

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous