{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:23:31Z","timestamp":1791296611514,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>\n              Mutations in\n              <jats:italic>NOTCH3<\/jats:italic>\n              cause cerebral autosomal\u2013dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common monogenic cause of stroke and vascular dementia. Misfolding and aggregation of NOTCH3 proteins triggered by cysteine-affecting mutations are considered to be the key disease mechanisms. However, the significance of cysteine-sparing mutations is still debated.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>\n              We studied a family with inherited small vessel disease by standardized medical history, clinical examination, MRI, ultrastructural analysis of skin biopsies, and Sanger sequencing of all\n              <jats:italic>NOTCH3<\/jats:italic>\n              exons. In addition, we performed in vitro characterization of\n              <jats:italic>NOTCH3<\/jats:italic>\n              variants using recombinant protein fragments and a single-particle aggregation assay.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>\n              We identified a novel cysteine-sparing\n              <jats:italic>NOTCH3<\/jats:italic>\n              mutation (D80G) in 4 family members, which was absent in a healthy sibling. All mutation carriers exhibited a CADASIL typical brain imaging and clinical phenotype, whereas skin biopsy showed inconsistent results. In vitro aggregation behavior of the D80G mutant was similar compared with cysteine-affecting mutations. This was reproduced with cysteine-sparing mutations from previously reported families having a phenotype consistent with CADASIL.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Our findings support the view that cysteine-sparing mutations, such as D80G, might cause CADASIL with a phenotype largely indistinguishable from cysteine mutations. The in vitro aggregation analysis of atypical\n              <jats:italic>NOTCH3<\/jats:italic>\n              mutations offers novel insights into pathomechanisms and might represent a tool for estimating their clinical significance.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.114.007472","type":"journal-article","created":{"date-parts":[[2015,1,21]],"date-time":"2015-01-21T07:12:58Z","timestamp":1421824378000},"page":"786-792","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":51,"title":["Cysteine-Sparing CADASIL Mutations in\n            <i>NOTCH3<\/i>\n            Show Proaggregatory Properties In Vitro"],"prefix":"10.1161","volume":"46","author":[{"given":"Frank Arne","family":"Wollenweber","sequence":"first","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Hanecker","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bayer-Karpinska","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Malik","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00f6rg","family":"B\u00e4zner","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Moreton","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith W.","family":"Muir","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany (H.B.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom (F.M., K.W.M.); Department of Neurology, Klinikum am..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Giese","sequence":"additional","affiliation":[{"name":"From the Institute for Stroke and Dementia Research, Klinikum der Universit\u00e4t M\u00fcnchen (F.A.W., P.H., A.B.-K., R.M., C.O., M.D., C.H., M.D.), Institute for Pathology (S.M.), and Center for Neuropathology and Prion Research (A.G.), Ludwig-Maximilians-University, Munich, Germany; 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