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

October 01, 2022

Joohyun Park 1, Arianna Tucci 2, Valentina Cipriani 3, German Demidov 1, Clarissa Rocca 4, Jan Senderek 5, Michaela Butryn 6, Ana Velic 7, Tanya Lam 8, Evangelia Galanaki 4, Elisa Cali 4, Letizia Vestito 2, Reza Maroofian 4, Natalie Deininger 1, Maren Rautenberg 1, Jakob Admard 1, Gesa-Astrid Hahn 9, Claudius Bartels 10, Nienke J H van Os 11, Rita Horvath 12, Patrick F Chinnery 13, May Yung Tiet 12, Channa Hewamadduma 14, Marios Hadjivassiliou 15, George K Tofaris 16; Genomics England Research Consortium; Nicholas W Wood 17, Stefanie N Hayer 18, Friedemann Bender 18, Benita Menden 1, Isabell Cordts 19, Katrin Klein 1, Huu Phuc Nguyen 20, Joachim K Krauss 21, Christian Blahak 22, Tim M Strom 23, Marc Sturm 1, Bart van de Warrenburg 11, Holger Lerche 24, Boris Maček 7, Matthis Synofzik 18, Stephan Ossowski 1, Dagmar Timmann 25, Marc E Wolf 26, Damian Smedley 2, Olaf Riess 27, Ludger Schöls 28, Henry Houlden 29, Tobias B Haack 27, Holger Hengel 30

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.

  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.