{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T01:20:21Z","timestamp":1770686421326,"version":"3.49.0"},"reference-count":17,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,7,18]],"date-time":"2024-07-18T00:00:00Z","timestamp":1721260800000},"content-version":"vor","delay-in-days":199,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ataxia Charlevoix\u2013Saguenay Foundation"},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["#RF-2019-12370417"],"award-info":[{"award-number":["#RF-2019-12370417"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Senior Clinical Researcher mandate of the Research Fund\u2014Flanders","award":["1805021N"],"award-info":[{"award-number":["1805021N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay is a rare neurodegenerative disease caused by biallelic variants in the SACS gene encoding for sacsin. More than 200 pathogenic variants have been identified to date, most of which are missense. It is likely that the prevalence of autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay is underestimated due to the lack of an efficient diagnostic tool able to validate variants of uncertain significance. We have previously shown that sacsin is almost absent in fibroblasts of patients with autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay regardless of the type of SACS variant, because sacsin carrying missense variants is cotranslationally degraded. In this work, we aimed to establish the pathogenicity of SACS variants by quantifying sacsin protein in blood samples, with relevant implications for autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay diagnosis. We developed a protocol to assess sacsin protein levels by western blot using small amounts of peripheral blood mononuclear cells, which can be propagated in culture and cryopreserved. The study involves eight patients with autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay (including a novel case) carrying variants of different types and positions along the SACS gene and two parents who are carriers of heterozygous missense variants. We show that patients with autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay (carrying either missense or truncating variants) almost completely lacked sacsin in peripheral blood mononuclear cells. Moreover, both carriers of a SACS missense variant showed 50% reduction in sacsin protein levels compared to controls. We also describe a patient with uniparental isodisomy carrying a homozygous nonsense variant near the 3\u2032 end of the SACS gene. This resulted in a stable sacsin protein lacking the last 202 amino acids, probably due to escape of nonsense-mediated decay of mRNA. In conclusion, we have optimized a minimally invasive diagnostic tool for autosomal recessive spastic ataxia of Charlevoix\u2013Saguenay in blood samples based on sacsin protein level assessment. Indeed, our results provide definite evidence that sacsin carrying missense pathogenic variants undergoes cotranslational degradation. The quantitative reduction in sacsin levels in the case of missense variants of uncertain significance allows defining them as pathogenic variants, something which cannot be predicted bioinformatically with high certainty.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae243","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T22:07:35Z","timestamp":1721254055000},"source":"Crossref","is-referenced-by-count":3,"title":["Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix\u2013Saguenay"],"prefix":"10.1093","volume":"6","author":[{"given":"Daniele","family":"De Ritis","sequence":"first","affiliation":[{"name":"Mitochondrial Dysfunctions in Neurodegeneration Unit, IRCCS Ospedale San Raffaele , 20132 Milan , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Ferr\u00e8","sequence":"additional","affiliation":[{"name":"Department of Neurology, IRCCS Ospedale San Raffaele , 20132 Milan , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"De Winter","sequence":"additional","affiliation":[{"name":"Institute Born-Bunge and Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , 2610 Antwerp , Belgium"},{"name":"Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital , 2610 Antwerp , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e9mence","family":"Tremblay-Desbiens","sequence":"additional","affiliation":[{"name":"Neuroscience Axis, CHU de Qu\u00e9bec, Universit\u00e9 Laval , Quebec City, QC G1V 0A6 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathieu","family":"Blais","sequence":"additional","affiliation":[{"name":"Neuroscience Axis, CHU de Qu\u00e9bec, Universit\u00e9 Laval , Quebec City, QC G1V 0A6 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Teresa","family":"Bassi","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Scientific Institute, IRCCS E. Medea , 23842 Bosisio Parini , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Dupr\u00e9","sequence":"additional","affiliation":[{"name":"Neuroscience Axis, CHU de Qu\u00e9bec, Universit\u00e9 Laval , Quebec City, QC G1V 0A6 , Canada"},{"name":"Department of Medicine, Faculty of Medicine, Universit\u00e9 Laval , Quebec City, QC G1V 0A6 , Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Baets","sequence":"additional","affiliation":[{"name":"Institute Born-Bunge and Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , 2610 Antwerp , Belgium"},{"name":"Department of Neurology, Neuromuscular Reference Centre, Antwerp University Hospital , 2610 Antwerp , Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-0479","authenticated-orcid":false,"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Department of Neurology, IRCCS Ospedale San Raffaele , 20132 Milan , Italy"},{"name":"Universit\u00e0 Vita-Salute San Raffaele , 20132 Milan , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8095-8208","authenticated-orcid":false,"given":"Francesca","family":"Maltecca","sequence":"additional","affiliation":[{"name":"Mitochondrial Dysfunctions in Neurodegeneration Unit, IRCCS Ospedale San Raffaele , 20132 Milan , Italy"},{"name":"Universit\u00e0 Vita-Salute San Raffaele , 20132 Milan , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,7,18]]},"reference":[{"key":"2024083010263038700_fcae243-B1","volume-title":"GeneReviews\u00ae 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