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

October 01, 2022

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


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.