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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: August 19, 2022
Accepted:
July 3,
2022
Received in revised form:
July 3,
2022
Received:
March 2,
2022
Footnotes
Joohyun Park, Arianna Tucci, and Valentina Cipriani contributed equally.
Henry Houlden, Tobias B. Haack, and Holger Hengel contributed equally.
Identification
Copyright
© 2022 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.
