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Tucci, Arianna; Cipriani, Valentina; Demidov, German; Rocca, Clarissa; Senderek, Jan; Butryn, Michaela; Lam, Tanya; Cali, Elisa; Vestito, Letizia; Maroofian, Reza; Deininger, Natalie; Rautenberg, Maren; Admard, Jakob; Bartels, Claudius; Horvath, Rita; Chinnery, Patrick F.; Tiet, May Yung; Hewamadduma, Channa; Tofaris, George K.; Ambrose, J.C.; Arumugam, P.; Baple, E.L.; Bleda, M.; Boardman-Pretty, F.; Boissiere, J.M.; Boustred, C.R.; Brittain, H.; Caulfield, M.J.; Craig, C.E.H.; Daugherty, L.C.; Devereau, A.; Elgar, G.; Foulger, R.E.; Fowler, T.; Furió-Tarí, P.; Hackett, J.M.; Halai, D.; Hamblin, A.; Henderson, S.; Holman, J.E.; Ibáñez, K.; Jackson, R.; Jones, L.J.; Kasperaviciute, D.; Kayikci, M.; Lahnstein, L.; Lawson, K.; Leigh, S.E.A.; Leong, I.U.S.; Maleady-Crowe, F.; Mason, J.; McDonagh, E.M.; Moutsianas, L.; Mueller, M.; Odhams, C.A.; Patch, C.; Perez-Gil, D.; Pullinger, J.; Rahim, T.; Riesgo-Ferreiro, P.; Rogers, T.; Ryten, M.; Sawant, K.; Scott, R.H.; Siddiq, A.; Sieghart, A.; Smedley, D.; Smith, K.R.; Spooner, W.; Stevens, H.E.; Stuckey, A.; Sultana, R.; Thomas, E.R.A.; Tucci, A.; Watters, S.A.; Welland, M.J.; Williams, E.; Zarowiecki, M.; Wood, Nicholas W.; Hayer, Stefanie N.; Bender, Friedemann; Menden, Benita; Cordts, Isabell; Klein, Katrin; Krauss, Joachim K.; Blahak, Christian; Strom, Tim M.; Sturm, Marc; van de Warrenburg, Bart; Lerche, Holger; Maček, Boris; Ossowski, Stephan; Timmann, Dagmar; Wolf, Marc E.; Smedley, Damian; Riess, Olaf; Schöls, Ludger; Houlden, Henry; Haack, Tobias B.; Hengel, Holger
Genetics in medicine, October 2022, 2022-10-00, 20221001, Letnik: 24, Številka: 10Journal Article
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. 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. 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. Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia. Display omitted
