PuSH - Publication Server of Helmholtz Zentrum München: Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.

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Park, J.* ; Tucci, A.* ; Cipriani, V.* ; Demidov, G.* ; Rocca, C.* ; Senderek, J.* ; Velic, A.* ; Lam, T.H.* ; Galanaki, E.* ; Cali, E.* ; Vestito, L.* ; Maroofian, R.* ; Deininger, N.* ; Rautenberg, M.* ; Admard, J.* ; Hahn, G.A.* ; Bartels, C.* ; van Os, N.J.H.* ; Horvath, R.* ; Chinnery, P.F.* ; Tiet, M.Y.* ; Hewamadduma, C.* ; Hadjivassiliou, M.* ; Tofaris, G.K.* ; Wood, S.M.* ; Zarowiecki, M.* ; Wood, N.W.* ; Hayer, S.N.* ; Krauss, J.L.* ; Strom, T.M. ; Sturm, M.* ; van de Warrenburg, B.P.* ; Lerche, H.* ; Synofzik, M.* ; Ossowski, S.* ; Timmann, D.* ; Smedley, D.* ; Riess, O.* ; Schöls, L.* ; Houlden, H.* ; Haack, T.B.* ; Hengel, H.*

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

Genet. Med. 24, 2079-2090 (2022)

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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.

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