| Title: |
Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy |
| Authors: |
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, G-A; Bartels, C; van Os, NJH; Horvath, R; Chinnery, PF; Tiet, MY; Hewamadduma, C; Hadjivassiliou, M; Tofaris, GK; Consortium, Genomics England Research; 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 |
| Publisher Information: |
Elsevier |
| Publication Year: |
2022 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://doi.org/10.1016/j.gim.2022.07.006 |
| DOI: |
10.1016/j.gim.2022.07.006 |
| Availability: |
https://doi.org/10.1016/j.gim.2022.07.006; https://ora.ox.ac.uk/objects/uuid:e7de5714-e03d-4cb2-8e67-2a95601e9adf |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.3F0BDE07 |
| Database: |
BASE |