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 G-A., Bartels C., van Os NJH., Horvath R., Chinnery PF., Tiet MY., Hewamadduma C., Hadjivassiliou M., Tofaris GK., Genomics England Research Consortium None., 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.
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.