{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T11:02:36Z","timestamp":1783335756549,"version":"3.54.6"},"reference-count":35,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose\u2014<\/jats:title>\n            <jats:p>\n              Homozygous and compound heterozygous mutations in the high temperature requirement serine peptidase A1 gene (\n              <jats:italic>HTRA1<\/jats:italic>\n              ) cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy. However, heterozygous\n              <jats:italic>HTRA1<\/jats:italic>\n              mutations were recently identified to be associated with autosomal dominant cerebral small vessel disease (SVD). The present study aims at investigating the clinical features, frequency, and spectrum of\n              <jats:italic>HTRA1<\/jats:italic>\n              mutations in a Taiwanese cohort with SVD.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods\u2014<\/jats:title>\n            <jats:p>\n              Mutational analyses of\n              <jats:italic>HTRA1<\/jats:italic>\n              were performed by Sanger sequencing in 222 subjects, selected from a cohort of 337 unrelated patients with SVD after excluding those harboring a\n              <jats:italic>NOTCH3<\/jats:italic>\n              mutation. The influence of these mutations on HTRA1 protease activities was characterized.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results\u2014<\/jats:title>\n            <jats:p>\n              Seven novel heterozygous mutations in\n              <jats:italic>HTRA1<\/jats:italic>\n              were identified, including p.Gly120Asp, p.Ile179Asn, p.Ala182Profs*33, p.Ile256Thr, p.Gly276Ala, p.Gln289Ter, and p.Asn324Thr, and each was identified in 1 single index patient. All mutations significantly compromise the HTRA1 protease activities. For the 7 index cases and another 2 affected siblings carrying a heterozygous\n              <jats:italic>HTRA1<\/jats:italic>\n              mutation, the common clinical presentations include lacunar infarction, intracerebral hemorrhage, cognitive decline, and spondylosis at the fifth to sixth decade of life. Among the 9 patients, 4 have psychiatric symptoms as delusion, depression, and compulsive behavior, 3 have leukoencephalopathy in anterior temporal poles, and 2 patients have alopecia.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Heterozygous\n              <jats:italic>HTRA1<\/jats:italic>\n              mutations account for 2.08% (7 of 337) of SVD in Taiwan. The clinical and neuroradiological features of\n              <jats:italic>HTRA1<\/jats:italic>\n              -related SVD and sporadic SVD are similar. These findings broaden the mutational spectrum of\n              <jats:italic>HTRA1<\/jats:italic>\n              and highlight the pathogenic role of heterozygous\n              <jats:italic>HTRA1<\/jats:italic>\n              mutations in SVD.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.118.021283","type":"journal-article","created":{"date-parts":[[2018,6,12]],"date-time":"2018-06-12T09:05:07Z","timestamp":1528794307000},"page":"1593-1601","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["Characterization of Heterozygous\n            <i>HTRA1<\/i>\n            Mutations in Taiwanese Patients With Cerebral Small Vessel Disease"],"prefix":"10.1161","volume":"49","author":[{"given":"Yi-Chung","family":"Lee","sequence":"first","affiliation":[{"name":"From the Departments of Neurology (Y.-C.L., C.-P.C., N.-C.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Taipei Veterans General Hospital, Taiwan; and Department of Neurology (Y.-C.L., C.-P.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Brain Research Center (Y.-C.L., J.-L.F., B.-W.S.), National Yang-Ming University School of Medicine, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Ping","family":"Chung","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (Y.-C.L., C.-P.C., N.-C.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Taipei Veterans General Hospital, Taiwan; and Department of Neurology (Y.-C.L., C.-P.C., J.-L.F., B.-W.S., Y.-C.L.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Chen","family":"Chao","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (Y.-C.L., C.-P.C., N.-C.C., J.-L.F., B.-W.S., Y.-C.L.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Ling","family":"Fuh","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (Y.-C.L., C.-P.C., N.-C.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Taipei Veterans General Hospital, Taiwan; and Department of Neurology (Y.-C.L., C.-P.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Brain Research Center (Y.-C.L., J.-L.F., B.-W.S.), National Yang-Ming University School of Medicine, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Chi","family":"Chang","sequence":"additional","affiliation":[{"name":"Radiology (F.-C.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Wing","family":"Soong","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (Y.-C.L., C.-P.C., N.-C.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Taipei Veterans General Hospital, Taiwan; and Department of Neurology (Y.-C.L., C.-P.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Brain Research Center (Y.-C.L., J.-L.F., B.-W.S.), National Yang-Ming University School of Medicine, Taipei, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chu","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Departments of Neurology (Y.-C.L., C.-P.C., N.-C.C., J.-L.F., B.-W.S., Y.-C.L.)"},{"name":"Taipei Veterans General Hospital, Taiwan; 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