{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:26:28Z","timestamp":1792715188992,"version":"4.5.0"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2001,1,2]]},"abstract":"<jats:p>\n            <jats:italic>Background<\/jats:italic>\n            \u2014We report hypertrophic cardiomyopathy (HCM) in a Spanish-American family caused by a novel \u03b1-tropomyosin (\n            <jats:italic>TPM1)<\/jats:italic>\n            mutation and examine the pathogenesis of the clinical disease by characterizing functional defects in the purified mutant protein.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Methods and Results<\/jats:italic>\n            \u2014HCM was linked to the\n            <jats:italic>TPM1<\/jats:italic>\n            gene (logarithm of the odds [LOD] score 3.17). Sequencing and restriction digestion analysis demonstrated a\n            <jats:italic>TPM1<\/jats:italic>\n            mutation V95A that cosegregated with HCM. The mutation has been associated with 13 deaths in 26 affected members (11 sudden deaths and 2 related to heart failure), with a cumulative survival rate of 73\u00b110% at the age of 40 years. Left ventricular wall thickness (mean 16\u00b16 mm) and disease penetrance (53%) were similar to those for the \u03b2-myosin mutations L908V and G256E previously associated with a benign prognosis. Left ventricular hypertrophy was milder than with the \u03b2-myosin mutation R403Q, but the prognosis was similarly poor. With the use of recombinant tropomyosins, we identified several functional alterations at the protein level. The mutation caused a 40% to 50% increase in calcium affinity in regulated thin filament\u2013myosin subfragment-1 (S1) MgATPase assays, a 20% decrease in MgATPase rates in the presence of saturating calcium, a 5% decrease in unloaded shortening velocity in in vitro motility assays, and no change in cooperative myosin S1 binding to regulated thin filaments.\n          <\/jats:p>\n          <jats:p>\n            <jats:italic>Conclusions<\/jats:italic>\n            \u2014In contrast to other reported\n            <jats:italic>TPM1<\/jats:italic>\n            mutations, V95A-associated HCM exhibits unusual features of mild phenotype but poor prognosis. Both myosin cycling and calcium binding to troponin are abnormal in the presence of the mutant tropomyosin. The genetic diagnosis afforded by this mutation will be valuable in the management of HCM.\n          <\/jats:p>","DOI":"10.1161\/01.cir.103.1.65","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:09:32Z","timestamp":1339459772000},"page":"65-71","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":110,"title":["Hypertrophic Cardiomyopathy Caused by a Novel \u03b1-Tropomyosin Mutation (V95A) Is Associated With Mild Cardiac Phenotype, Abnormal Calcium Binding to Troponin, Abnormal Myosin Cycling, and Poor Prognosis"],"prefix":"10.1161","volume":"103","author":[{"given":"Akihiko","family":"Karibe","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry S.","family":"Tobacman","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Strand","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Butters","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Back","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda L.","family":"Bachinski","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew E.","family":"Arai","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Ortiz","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Roberts","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Earl","family":"Homsher","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; Department of Physiology (N.B., E.H.), University of California, Los Angeles; and National Heart, Lung, and Blood Institute (A.E.A., A.O., L.F.), National Institutes of Health, Bethesda, Md."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lameh","family":"Fananapazir","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Baylor College of Medicine (A.K., L.L.B., R.R.), Houston, Tex; Departments of Internal Medicine (L.S.T., J.S., C.B.) and Biochemistry (L.S.T.), University of Iowa, Iowa City, Iowa; 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