{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T07:03:49Z","timestamp":1789715029174,"version":"4.0.1"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Transthyretin amyloid cardiomyopathy is a progressive infiltrative cardiomyopathy driven by the deposition of amyloid fibrils derived from destabilized transthyretin (TTR). Although several pathogenic\n                      <jats:italic toggle=\"no\">TTR<\/jats:italic>\n                      variants have been characterized, the clinical significance and molecular behavior of rare mutations remain poorly understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">A 31\u2010year\u2010old woman with early\u2010onset transthyretin amyloid cardiomyopathy and her family members were evaluated. Whole\u2010exome sequencing identified the G47R variant, which was validated and quantified in the proband and relatives using droplet\u2010digital polymerase chain reaction and amplicon\u2010based next\u2010generation sequencing. Biophysical assays assessed the thermodynamic and kinetic stability of G47R\u2010TTR. Aggregate formation assays evaluated the ability of small\u2010molecule kinetic stabilizers, exemplified by tafamidis, to suppress amyloid aggregation in\u00a0vitro. Plasma TTR tetramer concentrations in the proband and her asymptomatic heterozygous sister were measured using an ultraperformance liquid chromatography\u2013based assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">A heterozygous G47R substitution was confirmed in the family. Both homozygous G47R\u2010TTR and heterozygous G47R: wild\u2010type TTR exhibited significantly reduced thermodynamic and kinetic stability, comparable to the aggressive L55P variant. Tafamidis effectively suppressed aggregate formation of G47R\u2010TTR in\u00a0vitro. Plasma TTR tetramers were markedly reduced in both the symptomatic proband and the asymptomatic carrier, with tafamidis treatment in the proband restoring tetramer concentrations toward physiological levels and improving exercise tolerance and heart failure symptoms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      G47R represents a pathogenic\n                      <jats:italic toggle=\"no\">TTR<\/jats:italic>\n                      mutation characterized by substantial structural destabilization and amyloidogenicity, consistent with early\u2010onset disease. These findings highlight the clinical relevance of genotype\u2010informed biochemical characterization and support the potential of TTR tetramer concentration as a biomarker for disease severity and therapeutic response.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.044745","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:08:56Z","timestamp":1778756936000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Pathogenic Characterization of a Novel G47R Transthyretin Mutation in Early\u2010Onset Amyloid Cardiomyopathy"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3858-3869","authenticated-orcid":false,"given":"Bo","family":"Wang","sequence":"first","affiliation":[{"name":"Henan Province Clinical Research Center for Cardiovascular Diseases","place":["Zhengzhou, China"]},{"name":"University of Alabama 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